@article{code_qiu_solov'yov_lee_shin_roland_sagui_houde_rand_jorgensen_2023, title={Conformationally Restricted Glycopeptide Backbone Inhibits Gas-Phase H/D Scrambling between Glycan and Peptide Moieties}, ISSN={["1520-5126"]}, DOI={10.1021/jacs.3c04068}, abstractNote={Protein glycosylation is a common post-translational modification on extracellular proteins. The conformational dynamics of several glycoproteins have been characterized by hydrogen/deuterium exchange mass spectrometry (HDX-MS). However, it is, in most cases, not possible to extract information about glycan conformation and dynamics due to the general difficulty of separating the deuterium content of the glycan from that of the peptide (in particular, for O-linked glycans). Here, we investigate whether the fragmentation of protonated glycopeptides by collision-induced dissociation (CID) can be used to determine the solution-specific deuterium content of the glycan. Central to this concept is that glycopeptides can undergo a facile loss of glycans upon CID, thereby allowing for the determination of their masses. However, an essential prerequisite is that hydrogen and deuterium (H/D) scrambling can be kept in check. Therefore, we have measured the degree of scrambling upon glycosidic bond cleavage in glycopeptides that differ in the conformational flexibility of their backbone and glycosylation pattern. Our results show that complete scrambling precedes the glycosidic bond cleavage in normal glycopeptides derived from a glycoprotein; i.e., all labile hydrogens have undergone positional randomization prior to loss of the glycan. In contrast, the glycosidic bond cleavage occurs without any scrambling in the glycopeptide antibiotic vancomycin, reflecting that the glycan cannot interact with the peptide moiety due to a conformationally restricted backbone as revealed by molecular dynamics simulations. Scrambling is also inhibited, albeit to a lesser degree, in the conformationally restricted glycopeptides ristocetin and its pseudoaglycone, demonstrating that scrambling depends on an intricate interplay between the flexibility and proximity of the glycan and the peptide backbone.}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Code, Christian and Qiu, Danwen and Solov'yov, Ilia A. and Lee, Jung-Goo and Shin, Hyeon-Cheol and Roland, Christopher and Sagui, Celeste and Houde, Damian and Rand, Kasper D. and Jorgensen, Thomas J. D.}, year={2023}, month={Oct} }
 @article{xu_zhang_pan_mahn_roland_sagui_weninger_2023, title={Frustration Between Preferred States of Complementary Trinucleotide Repeat DNA Hairpins Anticorrelates with Expansion Disease Propensity}, volume={435}, ISSN={["1089-8638"]}, DOI={10.1016/j.jmb.2023.168086}, abstractNote={DNA trinucleotide repeat (TRs) expansion beyond a threshold often results in human neurodegenerative diseases. The mechanisms causing expansions remain unknown, although the tendency of TR ssDNA to self-associate into hairpins that slip along their length is widely presumed related. Here we apply single molecule FRET (smFRET) experiments and molecular dynamics simulations to determine conformational stabilities and slipping dynamics for CAG, CTG, GAC and GTC hairpins. Tetraloops are favored in CAG (89%), CTG (89%) and GTC (69%) while GAC favors triloops. We also determined that TTG interrupts near the loop in the CTG hairpin stabilize the hairpin against slipping. The different loop stabilities have implications for intermediate structures that may form when TR-containing duplex DNA opens. Opposing hairpins in the (CAG) ∙ (CTG) duplex would have matched stability whereas opposing hairpins in a (GAC) ∙ (GTC) duplex would have unmatched stability, introducing frustration in the (GAC) ∙ (GTC) opposing hairpins that could encourage their resolution to duplex DNA more rapidly than in (CAG) ∙ (CTG) structures. Given that the CAG and CTG TR can undergo large, disease-related expansion whereas the GAC and GTC sequences do not, these stability differences can inform and constrain models of expansion mechanisms of TR regions.}, number={10}, journal={JOURNAL OF MOLECULAR BIOLOGY}, author={Xu, Pengning and Zhang, Jiahui and Pan, Feng and Mahn, Chelsea and Roland, Christopher and Sagui, Celeste and Weninger, Keith}, year={2023}, month={May} }
 @article{kandola_venkatesan_zhang_lerbakken_von schulze_blanck_wu_unruh_berry_lange_et al._2023, title={Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal}, volume={12}, ISSN={["2050-084X"]}, DOI={10.7554/eLife.86939}, abstractNote={A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntington’s and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases.}, journal={ELIFE}, author={Kandola, Tej and Venkatesan, Shriram and Zhang, Jiahui and Lerbakken, Brooklyn T. and Von Schulze, Alex and Blanck, Jillian F. and Wu, Jianzheng and Unruh, Jay R. and Berry, Paula and Lange, Jeffrey J. and et al.}, year={2023}, month={Nov} }
 @article{fakharzadeh_qu_pan_sagui_roland_2023, title={Structure and Dynamics of DNA and RNA Double Helices Formed by d(CTG), d(GTC), r(CUG), and r(GUC) Trinucleotide Repeats and Associated DNA-RNA Hybrids}, ISSN={["1520-5207"]}, DOI={10.1021/acs.jpcb.3c03538}, abstractNote={Myotonic dystrophy type 1 is the most frequent form of muscular dystrophy in adults caused by an abnormal expansion of the CTG trinucleotide. Both the expanded DNA and the expanded CUG RNA transcript can fold into hairpins. Co-transcriptional formation of stable RNA·DNA hybrids can also enhance the instability of repeat tracts. We performed molecular dynamics simulations of homoduplexes associated with the disease, d(CTG)n and r(CUG)n, and their corresponding r(CAG)n:d(CTG)n and r(CUG)n:d(CAG)n hybrids that can form under bidirectional transcription and of non-pathological d(GTC)n and d(GUC)n homoduplexes. We characterized their conformations, stability, and dynamics and found that the U·U and T·T mismatches are dynamic, favoring anti-anti conformations inside the helical core, followed by anti-syn and syn-syn conformations. For DNA, the secondary minima in the non-expanding d(GTC)n helices are deeper, wider, and longer-lived than those in d(CTG)n, which constitutes another biophysical factor further differentiating the expanding and non-expanding sequences. The hybrid helices are closer to A-RNA, with the A-T and A-U pairs forming two stable Watson-Crick hydrogen bonds. The neutralizing ion distribution around the non-canonical pairs is also described.}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Fakharzadeh, Ashkan and Qu, Jing and Pan, Feng and Sagui, Celeste and Roland, Christopher}, year={2023}, month={Sep} }
 @article{man_he_nguyen_sagui_roland_xie_wang_2023, title={Unpolarized laser method for infrared spectrum calculation of amide I C=O bonds in proteins using molecular dynamics simulation}, volume={159}, ISSN={["1879-0534"]}, DOI={10.1016/j.compbiomed.2023.106902}, abstractNote={The investigation of the strong infrared (IR)-active amide I modes of peptides and proteins has received considerable attention because a wealth of detailed information on hydrogen bonding, dipole-dipole interactions, and the conformations of the peptide backbone can be derived from the amide I bands. The interpretation of experimental spectra typically requires substantial theoretical support, such as direct ab-initio molecular dynamics simulation or mixed quantum-classical description. However, considering the difficulties associated with these theoretical methods and their applications are limited in small peptides, it is highly desirable to develop a simple yet efficient approach for simulating the amide I modes of any large proteins in solution. In this work, we proposed a comprehensive computational method that extends the well-established molecular dynamics (MD) simulation method to include an unpolarized IR laser for exciting the CO bonds of proteins. We showed the amide I frequency corresponding to the frequency of the laser pulse which resonated with the CO bond vibration. At this frequency, the protein energy and the CO bond length fluctuation were maximized. Overall, the amide I bands of various single proteins and amyloids agreed well with experimental data. The method has been implemented into the AMBER simulation package, making it widely available to the scientific community. Additionally, the application of the method to simulate the transient amide I bands of amyloid fibrils during the IR laser-induced disassembly process was discussed in details.}, journal={COMPUTERS IN BIOLOGY AND MEDICINE}, author={Man, Viet Hoang and He, Xibing and Nguyen, Phuong H. and Sagui, Celeste and Roland, Christopher and Xie, Xiang-Qun and Wang, Junmei}, year={2023}, month={Jun} }
 @article{fakharzadeh_zhang_roland_sagui_2022, title={Novel eGZ-motif formed by regularly extruded guanine bases in a left-handed Z-DNA helix as a major motif behind CGG trinucleotide repeats}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gkac339}, abstractNote={Abstract}, journal={NUCLEIC ACIDS RESEARCH}, author={Fakharzadeh, Ashkan and Zhang, Jiahui and Roland, Christopher and Sagui, Celeste}, year={2022}, month={May} }
 @article{zhang_fakharzadeh_roland_sagui_2022, title={RNA as a Major-Groove Ligand: RNA-RNA and RNA-DNA Triplexes Formed by GAA and UUC or TTC Sequences}, volume={7}, ISSN={["2470-1343"]}, DOI={10.1021/acsomega.2c04358}, abstractNote={Friedreich’s ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.}, number={43}, journal={ACS OMEGA}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Roland, Christopher and Sagui, Celeste}, year={2022}, month={Nov}, pages={38728–38743} }
 @article{zhang_fakharzadeh_pan_roland_sagui_2021, title={Construction of DNA/RNA Triplex Helices Based on GAA/TTC Trinucleotide Repeats}, volume={11}, ISSN={["2331-8325"]}, DOI={10.21769/BioProtoc.4155}, abstractNote={Atypical DNA and RNA secondary structures play a crucial role in simple sequence repeat (SSR) diseases, which are associated with a class of neurological and neuromuscular disorders known as "anticipation diseases," where the age of disease onset decreases and the severity of the disease is increased as the intergenerational expansion of the SSR increases. While the mechanisms underlying these diseases are complex and remain elusive, there is a consensus that stable, non-B-DNA atypical secondary structures play an important - if not causative - role. These structures include single-stranded DNA loops and hairpins, G-quartets, Z-DNA, triplex nucleic acid structures, and others. While all of these structures are of interest, structures based on nucleic acid triplexes have recently garnered increased attention as they have been implicated in gene regulation, gene repair, and gene engineering. Our work here focuses on the construction of DNA triplexes and RNA/DNA hybrids formed from GAA/TTC trinucleotide repeats, which underlie Friedreich's ataxia. While there is some software, such as the Discovery Studio Visualizer, that can aid in the initial construction of DNA triple helices, the only option for the triple helix is constrained to be that of an antiparallel pyrimidine for the third strand. In this protocol, we illustrate how to build up more generalized DNA triplexes and DNA/RNA mixed hybrids. We make use of both the Discovery Studio Visualizer and the AMBER simulation package to construct the initial triplexes. Using the steps outlined here, one can - in principle - build up any triple nucleic acid helix with a desired sequence for large-scale molecular dynamics simulation studies.}, number={18}, journal={BIO-PROTOCOL}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Pan, Feng and Roland, Christopher and Sagui, Celeste}, year={2021}, month={Sep} }
 @misc{pan_zhang_xu_man_roland_weninger_sagui_2021, title={Molecular conformations and dynamics of nucleotide repeats associated with neurodegenerative diseases: double helices and CAG hairpin loops}, volume={19}, ISSN={["2001-0370"]}, DOI={10.1016/j.csbj.2021.04.037}, abstractNote={Pathogenic DNA secondary structures have been identified as a common and causative factor for expansion in trinucleotide, hexanucleotide, and other simple sequence repeats. These expansions underlie about fifty neurological and neuromuscular disorders known as “anticipation diseases”. Cell toxicity and death have been linked to the pathogenic conformations and functional changes of the RNA transcripts, of DNA itself and, when trinucleotides are present in exons, of the translated proteins. We review some of our results for the conformations and dynamics of pathogenic structures for both RNA and DNA, which include mismatched homoduplexes formed by trinucleotide repeats CAG and GAC; CCG and CGG; CTG(CUG) and GTC(GUC); the dynamics of DNA CAG hairpins; mismatched homoduplexes formed by hexanucleotide repeats (GGGGCC) and (GGCCCC); and G-quadruplexes formed by (GGGGCC) and (GGGCCT). We also discuss the dynamics of strand slippage in DNA hairpins formed by CAG repeats as observed with single-molecule Fluorescence Resonance Energy Transfer. This review focuses on the rich behavior exhibited by the mismatches associated with these simple sequence repeat noncanonical structures.}, journal={COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL}, author={Pan, Feng and Zhang, Yuan and Xu, Pengning and Man, Viet Hoang and Roland, Christopher and Weninger, Keith and Sagui, Celeste}, year={2021}, pages={2819–2832} }
 @article{tran_pan_tran_roland_sagui_2021, title={The F19W mutation reduces the binding affinity of the transmembrane A beta(11-40) trimer to the membrane bilayer}, volume={11}, ISSN={["2046-2069"]}, DOI={10.1039/d0ra08837d}, abstractNote={Dominant conformations of F19W 3Aβ11–40 immersed in transmembrane DPPC lipid bilayer submerged in aqueous solution.}, number={5}, journal={RSC ADVANCES}, author={Tran, Thanh Thuy and Pan, Feng and Tran, Linh and Roland, Christopher and Sagui, Celeste}, year={2021}, month={Jan}, pages={2664–2676} }
 @article{zhang_fakharzadeh_pan_roland_sagui_2020, title={Atypical structures of GAA/TTC trinucleotide repeats underlying Friedreich's ataxia: DNA triplexes and RNA/DNA hybrids}, volume={48}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gkaa665}, abstractNote={Abstract}, number={17}, journal={NUCLEIC ACIDS RESEARCH}, author={Zhang, Jiahui and Fakharzadeh, Ashkan and Pan, Feng and Roland, Christopher and Sagui, Celeste}, year={2020}, month={Sep}, pages={9899–9917} }
 @article{pan_zhang_man_roland_sagui_2018, title={E-motif formed by extrahelical cytosine bases in DNA homoduplexes of trinucleotide and hexanucleotide repeats}, volume={46}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gkx1186}, abstractNote={Abstract Atypical DNA secondary structures play an important role in expandable trinucleotide repeat (TR) and hexanucleotide repeat (HR) diseases. The cytosine mismatches in C-rich homoduplexes and hairpin stems are weakly bonded; experiments show that for certain sequences these may flip out of the helix core, forming an unusual structure termed an ‘e-motif’. We have performed molecular dynamics simulations of C-rich TR and HR DNA homoduplexes in order to characterize the conformations, stability and dynamics of formation of the e-motif, where the mismatched cytosines symmetrically flip out in the minor groove, pointing their base moieties towards the 5′-direction in each strand. TRs have two non-equivalent reading frames, (GCC)n and (CCG)n; while HRs have three: (CCCGGC)n, (CGGCCC)n, (CCCCGG)n. We define three types of pseudo basepair steps related to the mismatches and show that the e-motif is only stable in (GCC)n and (CCCGGC)n homoduplexes due to the favorable stacking of pseudo GpC steps (whose nature depends on whether TRs or HRs are involved) and the formation of hydrogen bonds between the mismatched cytosine at position i and the cytosine (TRs) or guanine (HRs) at position i − 2 along the same strand. We also characterize the extended e-motif, where all mismatched cytosines are extruded, their extra-helical stacking additionally stabilizing the homoduplexes.}, number={2}, journal={NUCLEIC ACIDS RESEARCH}, author={Pan, Feng and Zhang, Yuan and Man, Viet Hoang and Roland, Christopher and Sagui, Celeste}, year={2018}, month={Jan}, pages={942–955} }
 @article{zhang_roland_sagui_2018, title={Structural and Dynamical Characterization of DNA and RNA Quadruplexes Obtained from the GGGGCC and GGGCCT Hexanucleotide Repeats Associated with C9FTD/ALS and SCA36 Diseases}, volume={9}, ISSN={["1948-7193"]}, DOI={10.1021/acschemneuro.7b00476}, abstractNote={A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene has been considered the major cause behind both frontotemporal dementia and amyotrophic lateral sclerosis, while a (GGGCCT) is associated with spinocerebellar ataxia 36. Recent experiments involving NMR, CD, optical melting and 1D 1H NMR spectroscopy, suggest that the r(GGGGCC) HR can adopt a hairpin structure with G-G mismatches in equilibrium with a G-quadruplex structure. G-Quadruplexes have also been identified for d(GGGGCC). As these experiments lack molecular resolution, we have used molecular dynamics microsecond simulations to obtain a structural characterization of the G-quadruplexes associated with both HRs. All DNA G-quadruplexes, parallel or antiparallel, with or without loops are stable, while only parallel and one antiparallel (stabilized by diagonal loops) RNA G-quadruplexes are stable. It is known that antiparallel G-quadruplexes require alternating guanines to be in a syn conformation that is hindered by the C3'-endo pucker preferred by RNA. Initial RNA antiparallel quadruplexes built with C2'-endo sugars evolve such that the transition (C2'-endo)-to-(C3'-endo) triggers unwinding and buckling of the flat G-tetrads, resulting in the unfolding of the RNA antiparallel quadruplex. Finally, a parallel G-quadruplex stabilizes an adjacent C-tetrad in both DNA and RNA (thus effectively becoming a mixed quadruplex of 5 layers). The C-tetrad is stabilized by the stacking interactions with the preceding G-tetrad, by cyclical hydrogen bonds C(N4)-(O2), and by an ion between the G-tetrad and the C-tetrad. In addition, antiparallel DNA G-quadruplexes also stabilize flat C-layers at the ends of the quadruplexes.}, number={5}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Zhang, Yuan and Roland, Christopher and Sagui, Celeste}, year={2018}, month={May}, pages={1104–1117} }
 @article{pan_man_roland_sagui_2018, title={Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats}, volume={122}, ISSN={["1520-6106"]}, DOI={10.1021/acs.jpcb.8b01658}, abstractNote={Expansions of both GGC and CCG sequences lead to a number of expandable, trinucleotide repeat (TR) neurodegenerative diseases. Understanding of these diseases involves, among other things, the structural characterization of the atypical DNA and RNA secondary structures. We have performed molecular dynamics simulations of (GCC) n and (GGC) n homoduplexes in order to characterize their conformations, stability, and dynamics. Each TR has two reading frames, which results in eight nonequivalent RNA/DNA homoduplexes, characterized by CpG or GpC steps between the Watson-Crick base pairs. Free energy maps for the eight homoduplexes indicate that the C-mismatches prefer anti-anti conformations, while G-mismatches prefer anti-syn conformations. Comparison between three modifications of the DNA AMBER force field shows good agreement for the mismatch free energy maps. The mismatches in DNA-GCC (but not CCG) are extrahelical, forming an extended e-motif. The mismatched duplexes exhibit characteristic sequence-dependent step twist, with strong variations in the G-rich sequences and the e-motif. The distribution of Na+ is highly localized around the mismatches, especially G-mismatches. In the e-motif, there is strong Na+ binding by two G(N7) atoms belonging to the pseudo GpC step created when cytosines are extruded and by extrahelical cytosines. Finally, we used a novel technique based on fast melting by means of an infrared laser pulse to classify the relative stability of the different DNA-CCG and -GGC homoduplexes.}, number={16}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Pan, Feng and Man, Viet Hoang and Roland, Christopher and Sagui, Celeste}, year={2018}, month={Apr}, pages={4491–4512} }
 @article{zhang_roland_sagui_2017, title={Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases}, volume={8}, ISSN={["1948-7193"]}, DOI={10.1021/acschemneuro.6b00348}, abstractNote={A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs. G-rich helices share common features. The inner G-G mismatches stay inside the helix in Gsyn-Ganti conformations and form two hydrogen bonds (HBs) between the Watson-Crick edge of Ganti and the Hoogsteen edge of Gsyn. In addition, Gsyn in RNA forms a base-phosphate HB. Inner G-G mismatches cause local unwinding of the helix. G-rich double helices are more stable than C-rich helices due to better stacking and HBs of G-G mismatches. C-rich helix conformations vary wildly. C mismatches flip out of the helix in DNA but not in RNA. Least (most) stable C-rich RNA and DNA helices have single (double) mismatches separated by two (four) Watson-Crick basepairs. The most stable DNA structure displays an "e-motif" where mismatched bases flip toward the minor groove and point in the 5' direction. There are two RNA conformations, where the orientation and HB pattern of the mismatches is coupled to bending of the helix.}, number={3}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Zhang, Yuan and Roland, Christopher and Sagui, Celeste}, year={2017}, month={Mar}, pages={578–591} }
 @article{pan_man_roland_sagui_2017, title={Structure and Dynamics of DNA and RNA Double Helices of CAG and GAC Trinucleotide Repeats}, volume={113}, ISSN={["1542-0086"]}, DOI={10.1016/j.bpj.2017.05.041}, abstractNote={<h2>Abstract</h2> CAG trinucleotide repeats are known to cause 10 late-onset progressive neurodegenerative disorders as the repeats expand beyond a threshold, whereas GAC repeats are associated with skeletal dysplasias and expand from the normal five to a maximum of seven repeats. The TR secondary structure is believed to play a role in CAG expansions. We have carried out free energy and molecular dynamics studies to determine the preferred conformations of the A-A noncanonical pairs in (CAG)<sub>n</sub> and (GAC)<sub>n</sub> trinucleotide repeats (<i>n</i> = 1, 4) and the consequent changes in the overall structure of the RNA and DNA duplexes. We find that the global free energy minimum corresponds to A-A pairs stacked inside the core of the helix with anti-anti conformations in RNA and (high-anti)-(high-anti) conformations in DNA. The next minimum corresponds to anti-syn conformations, whereas syn-syn conformations are higher in energy. Transition rates of the A-A conformations are higher for RNA than DNA. Mechanisms for these various transitions are identified. Additional structural and dynamical aspects of the helical conformations are explored, with a focus on contrasting CAG and GAC duplexes. The neutralizing ion distribution around the noncanonical pairs is described.}, number={1}, journal={BIOPHYSICAL JOURNAL}, author={Pan, Feng and Man, Viet Hoang and Roland, Christopher and Sagui, Celeste}, year={2017}, month={Jul}, pages={19–36} }
 @article{zhang_man_roland_sagui_2016, title={Amyloid Properties of Asparagine and Glutamine in Prion-like Proteins}, volume={7}, ISSN={1948-7193 1948-7193}, url={http://dx.doi.org/10.1021/ACSCHEMNEURO.5B00337}, DOI={10.1021/acschemneuro.5b00337}, abstractNote={Sequences rich in glutamine (Q) and asparagine (N) are intrinsically disordered in monomeric form, but can aggregate into highly ordered amyloids, as seen in Q/N-rich prion domains (PrDs). Amyloids are fibrillar protein aggregates rich in β-sheet structures that can self-propagate through protein-conformational chain reactions. Here, we present a comprehensive theoretical study of N/Q-rich peptides, including sequences found in the yeast Sup35 PrD, in parallel and antiparallel β-sheet aggregates, and probe via fully atomistic molecular dynamics simulations all their possible steric-zipper interfaces in order to determine their protofibril structure and their relative stability. Our results show that polyglutamine aggregates are more stable than polyasparagine aggregates. Enthalpic contributions to the free energy favor the formation of polyQ protofibrils, while entropic contributions favor the formation of polyN protofibrils. The considerably larger phase space that disordered polyQ must sample on its way to aggregation probably is at the root of the associated slower kinetics observed experimentally. When other amino acids are present, such as in the Sup35 PrD, their shorter side chains favor steric-zipper formation for N but not Q, as they preclude the in-register association of the long Q side chains.}, number={5}, journal={ACS Chemical Neuroscience}, publisher={American Chemical Society (ACS)}, author={Zhang, Yuan and Man, Viet Hoang and Roland, Christopher and Sagui, Celeste}, year={2016}, month={Mar}, pages={576–587} }
 @article{man_pan_sagui_roland_2016, title={Comparative melting and healing of B-DNA and Z-DNA by an infrared laser pulse}, volume={144}, ISSN={["1089-7690"]}, DOI={10.1063/1.4945340}, abstractNote={We explore the use of a fast laser melting simulation approach combined with atomistic molecular dynamics simulations in order to determine the melting and healing responses of B-DNA and Z-DNA dodecamers with the same d(5′-CGCGCGCGCGCG-3′)2 sequence. The frequency of the laser pulse is specifically tuned to disrupt Watson-Crick hydrogen bonds, thus inducing melting of the DNA duplexes. Subsequently, the structures relax and partially refold, depending on the field strength. In addition to the inherent interest of the nonequilibrium melting process, we propose that fast melting by an infrared laser pulse could be used as a technique for a fast comparison of relative stabilities of same-sequence oligonucleotides with different secondary structures with full atomistic detail of the structures and solvent. This could be particularly useful for nonstandard secondary structures involving non-canonical base pairs, mismatches, etc.}, number={14}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Man, Viet Hoang and Pan, Feng and Sagui, Celeste and Roland, Christopher}, year={2016}, month={Apr} }
 @article{zhang_hoang man_roland_sagui_2016, title={Contrasting Roles of Asparagine and Glutamine in the Aggregation of Prion-Like Proteins}, volume={110}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/J.BPJ.2015.11.1191}, DOI={10.1016/J.BPJ.2015.11.1191}, abstractNote={Sequences rich in glutamine (Q) and asparagine (N) are intrinsically disordered in monomeric form, but can aggregate into highly ordered amyloids, as seen in Q/N-rich prion domains (PrDs). Amyloids are fibrillar protein aggregates rich in β-sheet structures that can self-propagate through protein-conformational chain reactions. It has been shown that tuning the amount of Ns and Qs in yeast PrDs results in very different effects: N-rich mutants lead to non-pathological self-seeding amyloids while Q-rich mutants lead to toxic nonamyloid structures. These structural preferences have been explained in terms of an enhanced β- hairpin turn propensity of Ns over Qs. Here, we consider a variety of N/Q-rich peptides, including sequences found in the yeast Sup35 PrD, in parallel and antiparallel β-sheet aggregates, and probe all their possible steric-zipper interfaces to determine their relative stability. Our results show that polyglutamine aggregates are more stable than polyasparagine aggregates. The observation that Q-rich PrD mutants lack amyloid structure can be attributed to three facts. First, although once formed polyglutamine aggregates are more stable, their entropic contribution to the free energy is less favorable: Q-rich sequences have a larger phase space to sample. Second, N-rich sequences favor parallel β sheets, for which the formation of hairpin turns is irrelevant: indeed polyasparagine β-hairpins are more unstable than polyglutamine hairpins. Third, when other amino acids are present, such as in the Sup35 PrD, their shorter side chains favor steric-zipper formation for N but not Q, as they preclude the in-register association of the long Q side chains.}, number={3}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Zhang, Yuan and Hoang Man, Viet and Roland, Christopher and Sagui, Celeste}, year={2016}, month={Feb}, pages={214a–215a} }
 @article{man_van-oanh_derreumaux_li_roland_sagui_nguyen_2016, title={Picosecond infrared laser-induced all-atom nonequilibrium molecular dynamics simulation of dissociation of viruses}, volume={18}, ISSN={["1463-9084"]}, DOI={10.1039/c5cp07711g}, abstractNote={Laser-induced all-atom nonequilibrium molecular dynamics simulation of virus dissociation.}, number={17}, journal={PHYSICAL CHEMISTRY CHEMICAL PHYSICS}, author={Man, Viet Hoang and Van-Oanh, Nguyen-Thi and Derreumaux, Philippe and Li, Mai Suan and Roland, Christopher and Sagui, Celeste and Nguyen, Phuong H.}, year={2016}, month={May}, pages={11951–11958} }
 @article{pan_man_roland_sagui_2016, title={Stability and Ion Distributions Around Left- and Right-Handed DNA and RNA Duplexes: A Comparative Study}, volume={110}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/J.BPJ.2015.11.2197}, DOI={10.1016/J.BPJ.2015.11.2197}, abstractNote={The determination of the relative stability of nucleic acids structures is often critical for the understanding of their molecular functions. Theoretically, the relative stability of polynucleotides is determined via free energy or thermal melting simulations. These quantities may, however, be computationally quite intensive and therefore challenging. As an interesting alternative, we explore the use of a non-equilibrium laser melting approach combined with molecular dynamics simulations in order to determine the relative stability of B-DNA and Z-DNA duplexes. Specifically, a fast laser pulse is applied to the d(5’-CGCGCGCGCGCG-3’)2 dodecamer in either form. A laser pulse, whose frequency is tuned to disrupt the Watson-Crick hydrogen bonds, is applied and induces a partial melting of the DNA duplexes. The subsequent structural relaxations and partial refolding is indicative of the greater stability of B-DNA in different aqueous environments. In addition, we have also carried out a detailed investigation of the ion atmosphere around both the B- and Z-DNA/RNA duplexes. This ion atmosphere is an intrinsic part of the structure of the solvated nucleic acids, but is difficult to probe experimentally. The ions investigated include Na+, K+, Mg2+, and Cl- in various concentrations. The simulations results quantitatively describe the characteristics of the ion distributions around the different nucleic acid structures. These, in turn, reflect the effect of the different ion types and the atomistic and structural elements of the nucleic acids, which are described and contrasted.}, number={3}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Pan, Feng and Man, Viet H. and Roland, Christopher and Sagui, Celeste}, year={2016}, month={Feb}, pages={407a} }
 @article{man_roland_sagui_2016, title={Structural Determinants of Polyqlutamine Protofibrils and Crystallites}, volume={110}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/J.BPJ.2015.11.1192}, DOI={10.1016/J.BPJ.2015.11.1192}, abstractNote={Nine inherited neurodegenerative diseases are associated with the expansion of the CAG codon. Once the translated polyglutamine expansion becomes longer than ∼36 residues, it triggers the formation of intraneural protein aggregates that often display the signature of cross-β amyloid fibrils. Here, we use fully atomistic molecular dynamics simulations with explicit solvent and state-of-the-art force field to probe the structural stability and conformational dynamics of both previously proposed and new polyglutamine aggregate models, for a cumulative time of over 23 μs. We estimate the relative stability of parallel and antiparallel β sheets, and characterize possible steric interfaces between neighboring sheets and the effects of different alignments of the side-chain carboxamide dipoles. The results indicate that (i) different initial oligomer structures converge to crystals consistent with available diffraction data, after undergoing cooperative side-chain rotational transitions and quarter-stagger displacements on a microsecond time scale, (ii) structures previously deemed stable on a hundred nanosecond time scale are unstable over the microsecond time scale, and (iii) conversely, structures previously deemed unstable did not account for the correct side-chain packing and once the correct symmetry is considered the structures become stable for over a microsecond, due to tightly interdigitated side chains, which lock into highly regular polar zippers with inter-side-chain and backbone−side-chain hydrogen bonds. With these insights, we built Q40 monomeric models with different combinations of arc and hairpin turns and tested them for stability. The stable monomers were further probed as a function of repeat length. Our results are consistent with the aggregation threshold. These results explain and reconcile previously reported experimental and model discrepancies about polyglutamine aggregate structures.}, number={3}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Man, Viet H. and Roland, Christopher and Sagui, Celeste}, year={2016}, month={Feb}, pages={215a} }
 @article{moradi_sagui_roland_2015, title={Calculating transition and reaction rates with nonequilibrium work measurements}, volume={640}, ISSN={["1742-6596"]}, DOI={10.1088/1742-6596/640/1/012014}, abstractNote={By combining elements of the nonequilibrium work theorem with Transition Path Theory (TPT), we have developed a formalism for investigating transition pathways and probabilities that may effectively be implemented by means of Steered Molecular Dynamics (SMD) simulations. The workings of this formalism are illustrated by means a simple example based on a diproline peptide.}, journal={XXVI IUPAP CONFERENCE ON COMPUTATIONAL PHYSICS (CCP2014)}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2015} }
 @article{viet_derreumaux_li_roland_sagui_nguyen_2015, title={Picosecond dissociation of amyloid fibrils with infrared laser: A nonequilibrium simulation study}, volume={143}, ISSN={["1089-7690"]}, DOI={10.1063/1.4933207}, abstractNote={Recently, mid-infrared free-electron laser technology has been developed to dissociate amyloid fibrils. Here, we present a theoretical framework for this type of experiment based on laser-induced nonequilibrium all-atom molecular dynamics simulations. We show that the fibril is destroyed due to the strong resonance between its amide I vibrational modes and the laser field. The effects of laser irradiation are determined by a balance between fibril formation and dissociation. While the overall rearrangements of the fibril finish over short time scales, the interaction between the peptides and the solvent continues over much longer times indicating that the waters play an important role in the dissociation process. Our results thus provide new insights into amyloid fibril dissociation by laser techniques and open up new venues to investigate the complex phenomena associated with amyloidogenesis.}, number={15}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Viet, Man Hoang and Derreumaux, Philippe and Li, Mai Suan and Roland, Christopher and Sagui, Celeste and Nguyen, Phuong H.}, year={2015}, month={Oct} }
 @article{viet_truong_derreumaux_li_roland_sagui_nguyen_2015, title={Picosecond melting of peptide nanotubes using an infrared laser: a nonequilibrium simulation study}, volume={17}, ISSN={["1463-9084"]}, DOI={10.1039/c5cp04401d}, abstractNote={Resonance between carboxylate bond vibrations and laser frequency results in melting of nanotube.}, number={41}, journal={PHYSICAL CHEMISTRY CHEMICAL PHYSICS}, author={Viet, Man Hoang and Truong, Phan Minh and Derreumaux, Philippe and Li, Mai Suan and Roland, Christopher and Sagui, Celeste and Nguyen, Phuong H.}, year={2015}, pages={27275–27280} }
 @article{zhang_sagui_2015, title={Secondary structure assignment for conformationally irregular peptides: Comparison between DSSP, STRIDE and KAKSI}, volume={55}, ISSN={["1873-4243"]}, DOI={10.1016/j.jmgm.2014.10.005}, abstractNote={Secondary structure assignment codes were built to explore the regularities associated with the periodic motifs of proteins, such as those in backbone dihedral angles or in hydrogen bonds between backbone atoms. Precise structure assignment is challenging because real-life secondary structures are susceptible to bending, twist, fraying and other deformations that can distance them from their geometrical prototypes. Although results from codes such as DSSP and STRIDE converge in well-ordered structures, the agreement between the secondary structure assignments is known to deteriorate as the conformations become more distorted. Conformationally irregular peptides therefore offer a great opportunity to explore the differences between these codes. This is especially important for unfolded proteins and intrinsically disordered proteins, which are known to exhibit residual and/or transient secondary structure whose characterization is challenging. In this work, we have carried out Molecular Dynamics simulations of (relatively) disordered peptides, specifically gp41659–671 (ELLELDKWASLWN), the homopeptide polyasparagine (N18), and polyasparagine dimers. We have analyzed the resulting conformations with DSSP and STRIDE, based on hydrogen-bond patterns (and dihedral angles for STRIDE), and KAKSI, based on α-Carbon distances; and carefully characterized the differences in structural assignments. The full-sequence Segment Overlap (SOV) scores, that quantify the agreement between two secondary structure assignments, vary from 70% for gp41659–671 (STRIDE as reference) to 49% for N18 (DSSP as reference). Major differences are observed in turns, in the distinction between α and 310 helices, and in short parallel-sheet segments.}, journal={JOURNAL OF MOLECULAR GRAPHICS & MODELLING}, author={Zhang, Yuan and Sagui, Celeste}, year={2015}, month={Feb}, pages={72–84} }
 @article{man_roland_sagui_2015, title={Structural Determinants of Polyglutamine Protofibrils and Crystallites}, volume={6}, ISSN={["1948-7193"]}, DOI={10.1021/cn500358g}, abstractNote={Nine inherited neurodegenerative diseases are associated with the expansion of the CAG codon. Once the translated polyglutamine expansion becomes longer than ~36 residues, it triggers the formation of intraneural protein aggregates that often display the signature of cross-β amyloid fibrils. Here, we use fully atomistic molecular dynamics simulations to probe the structural stability and conformational dynamics of both previously proposed and new polyglutamine aggregate models. We test the relative stability of parallel and antiparallel β sheets, and characterize possible steric interfaces between neighboring sheets and the effects of different alignments of the side-chain carboxamide dipoles. Results indicate that (i) different initial oligomer structures converge to crystals consistent with available diffraction data, after undergoing cooperative side-chain rotational transitions and quarter-stagger displacements on a microsecond time scale, (ii) structures previously deemed stable on a hundred nanosecond time scale are unstable over the microsecond time scale, and (iii) conversely, structures previously deemed unstable did not account for the correct side-chain packing and once the correct symmetry is considered the structures become stable for over a microsecond, due to tightly interdigitated side chains, which lock into highly regular polar zippers with inter-side-chain and backbone-side-chain hydrogen bonds. With these insights, we built Q40 monomeric models with different combinations of arc and hairpin turns and tested them for stability. The stable monomers were further probed as a function of repeat length. Our results are consistent with the aggregation threshold. These results explain and reconcile previously reported experimental and model discrepancies about polyglutamine aggregate structures.}, number={4}, journal={ACS CHEMICAL NEUROSCIENCE}, author={Man, Viet Hoang and Roland, Christopher and Sagui, Celeste}, year={2015}, month={Apr}, pages={632–645} }
 @article{moradi_babin_roland_sagui_2015, title={The Adaptively Biased Molecular Dynamics method revisited: New capabilities and an application}, volume={640}, ISSN={["1742-6596"]}, DOI={10.1088/1742-6596/640/1/012020}, abstractNote={The free energy is perhaps one of the most important quantity required for describing biomolecular systems at equilibrium. Unfortunately, accurate and reliable free energies are notoriously difficult to calculate. To address this issue, we previously developed the Adaptively Biased Molecular Dynamics (ABMD) method for accurate calculation of rugged free energy surfaces (FES). Here, we briefly review the workings of the ABMD method with an emphasis on recent software additions, along with a short summary of a selected ABMD application based on the B-to-Z DNA transition. The ABMD method, along with current extensions, is currently implemented in the AMBER (ver.10-14) software package.}, journal={XXVI IUPAP CONFERENCE ON COMPUTATIONAL PHYSICS (CCP2014)}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2015} }
 @misc{cisneros_karttunen_ren_sagui_2014, title={Classical Electrostatics for Biomolecular Simulations}, volume={114}, ISSN={["1520-6890"]}, DOI={10.1021/cr300461d}, abstractNote={Popelier and co-workers have developed the Quantum Chemical Topology Force Field (QCTFF), based on the Quantum Chemical Topology (QCT) method. The QCT method is a generalisation of the Quantum Theory of Atoms in Molecules, which generates topological atoms of finite size and particular shapes, using only the gradient of the electron density. QCTFF embraces multipolar electrostatics as a way to overcome the inherent limitations of point charge electrostatics. QCTFF captures polarisation effects (beyond dipole moments) through a machine learning method called kriging. Kriging establishes a direct mapping between a given atom's multipole moment and the coordinates of the atoms surrounding it. This procedure handles both inter1- and intramolecular2 polarisation. QCTFF handles the remaining non-electrostatic energy contributions by kriging, thereby offering a seamless treatment of all energy contributions. All training information is sampled from supermolecular clusters, thereby abandoning the framework of long-range perturbation theory that underpins some multipolar force fields. This decision makes the modelling of an ion in aqueous solution3 conceptually smooth4-10 . In principle, the method is independent of the basis used, and the QCT partitioning naturally treats charge penetration effects and charge transfer6. QCT multipolar electrostatic models have also been used in molecular dynamics simulation, albeit still in the rigid body context. The fully flexible case is feasible and currently being implemented in the program DL_POLY_4. The simulation work shows both quantitative and qualitative differences in spatial distribution functions calculated for liquid water11, aqueous imidazole12 and hydrated serine13, again demonstrating the need for multipole moments14.}, number={1}, journal={CHEMICAL REVIEWS}, author={Cisneros, G. Andres and Karttunen, Mikko and Ren, Pengyu and Sagui, Celeste}, year={2014}, month={Jan}, pages={779–814} }
 @article{cisneros_karttunen_ren_sagui_2014, title={Correction to Classical Electrostatics for Biomolecular Simulations}, volume={114}, ISSN={0009-2665 1520-6890}, url={http://dx.doi.org/10.1021/CR500124K}, DOI={10.1021/CR500124K}, abstractNote={ADVERTISEMENT RETURN TO ISSUEPREVAddition/CorrectionORIGINAL ARTICLEThis notice is a correctionCorrection to Classical Electrostatics for Biomolecular SimulationsG. Andrés Cisneros, Mikko Karttunen, Pengyu Ren, and Celeste Sagui*Cite this: Chem. Rev. 2014, 114, 9, 5116Publication Date (Web):April 8, 2014Publication History Published online8 April 2014Published inissue 14 May 2014https://doi.org/10.1021/cr500124kCopyright © 2014 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1078Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (120 KB) Get e-Alerts Get e-Alerts}, number={9}, journal={Chemical Reviews}, publisher={American Chemical Society (ACS)}, author={Cisneros, G. Andrés and Karttunen, Mikko and Ren, Pengyu and Sagui, Celeste}, year={2014}, month={Apr}, pages={5116–5116} }
 @article{moradi_sagui_roland_2014, title={Investigating rare events with nonequilibrium work measurements. I. Nonequilibrium transition path probabilities}, volume={140}, ISSN={0021-9606 1089-7690}, url={http://dx.doi.org/10.1063/1.4861055}, DOI={10.1063/1.4861055}, abstractNote={We have developed a formalism for investigating transition pathways and transition probabilities for rare events in biomolecular systems. In this paper, we set the theoretical framework for employing nonequilibrium work relations to estimate the relative reaction rates associated with different classes of transition pathways. Particularly, we derive an extension of Crook's transient fluctuation theorem, which relates the relative transition rates of driven systems in the forward and reverse directions, and allows for the calculation of these relative rates using work measurements (e.g., in Steered Molecular Dynamics). The formalism presented here can be combined with Transition Path Theory to relate the equilibrium and driven transition rates. The usefulness of this framework is illustrated by means of a Gaussian model and a driven proline dimer.}, number={3}, journal={The Journal of Chemical Physics}, publisher={AIP Publishing}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2014}, month={Jan}, pages={034114} }
 @article{moradi_sagui_roland_2014, title={Investigating rare events with nonequilibrium work measurements. I. Nonequilibrium transition path probabilities (vol 140, 034114, 2014)}, volume={140}, ISSN={["1089-7690"]}, DOI={10.1063/1.4865580}, abstractNote={First Page}, number={6}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2014}, month={Feb} }
 @article{moradi_sagui_roland_2014, title={Investigating rare events with nonequilibrium work measurements. II. Transition and reaction rates}, volume={140}, ISSN={0021-9606 1089-7690}, url={http://dx.doi.org/10.1063/1.4861056}, DOI={10.1063/1.4861056}, abstractNote={We present a formalism for investigating transition pathways and transition probabilities for rare events in biomolecular systems. The formalism is based on combining Transition Path Theory with the results of nonequilibrium work relations, and shows that the equilibrium and nonequilibrium transition rates are in fact related. Aside from its fundamental importance, this allows for the calculation of relative equilibrium reaction rates with driven nonequilibrium simulations such as Steered Molecular Dynamics. The workings of the formalism are illustrated with a few typical numerical examples.}, number={3}, journal={The Journal of Chemical Physics}, publisher={AIP Publishing}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2014}, month={Jan}, pages={034115} }
 @article{moradi_sagui_roland_2014, title={Investigating rare events with nonequilibrium work measurements. II. Transition and reaction rates (vol 140, 034115, 2014)}, volume={140}, ISSN={["1089-7690"]}, DOI={10.1063/1.4865582}, abstractNote={First Page}, number={6}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2014}, month={Feb} }
 @article{pan_roland_sagui_2014, title={Ion distributions around left- and right-handed DNA and RNA duplexes: a comparative study}, volume={42}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gku1107}, abstractNote={The ion atmosphere around nucleic acids is an integral part of their solvated structure. However, detailed aspects of the ionic distribution are difficult to probe experimentally, and comparative studies for different structures of the same sequence are almost non-existent. Here, we have used large-scale molecular dynamics simulations to perform a comparative study of the ion distribution around (5′-CGCGCGCGCGCG-3′)2 dodecamers in solution in B-DNA, A-RNA, Z-DNA and Z-RNA forms. The CG sequence is very sensitive to ionic strength and it allows the comparison with the rare but important left-handed forms. The ions investigated include Na+, K+ and Mg2 +, with various concentrations of their chloride salts. Our results quantitatively describe the characteristics of the ionic distributions for different structures at varying ionic strengths, tracing these differences to nucleic acid structure and ion type. Several binding pockets with rather long ion residence times are described, both for the monovalent ions and for the hexahydrated Mg[(H2O)6]2+ ion. The conformations of these binding pockets include direct binding through desolvated ion bridges in the GpC steps in B-DNA and A-RNA; direct binding to backbone oxygens; binding of Mg[(H2O)6]2+ to distant phosphates, resulting in acute bending of A-RNA; tight ‘ion traps’ in Z-RNA between C-O2 and the C-O2′ atoms in GpC steps; and others.}, number={22}, journal={NUCLEIC ACIDS RESEARCH}, author={Pan, Feng and Roland, Christopher and Sagui, Celeste}, year={2014}, month={Dec}, pages={13981–13996} }
 @article{zhang_sagui_2014, title={The gp41(659-671) HIV-1 Antibody Epitope: A Structurally Challenging Small Peptide}, volume={118}, ISSN={["1520-5207"]}, DOI={10.1021/jp409355r}, abstractNote={We report on extensive molecular dynamics (MD) simulations of the tridecapeptide corresponding to residues 659-671 of the envelope glycoprotein gp41 of HIV-1, which spans the 2F5 monoclonal antibody epitope ELDKWA. Previously, X-ray crystallography, nuclear magnetic resonance, and circular dichroism experiments have yielded conflicting conformational information, but there is a growing consensus that the monomeric peptide in aqueous solution is disordered. Here, we use the latest, state-of-the-art AMBER force fields to describe the complex conformational landscape of gp41(659-671). We have analyzed the conformational ensembles of the peptide in solution both without applied restraints and under successive tensile restraints. In contrast to previous MD simulations, our results are consistent with the bulk of the experimental findings. The amount of helical population is important in aqueous solution, but this structure forms part of a flexible conformational ensemble with a rugged free energy landscape with shallow minima. Under uniaxial tension, the disordered peptide first becomes fully helical before melting into turns, loops, and 310-helices. The conformational ensemble includes epitope conformations close to an NMR solution structure (PDB ID 1LCX ) as well as epitope conformations close to a very different, extended crystal structure (PDB ID 1TJH ).}, number={1}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Zhang, Yuan and Sagui, Celeste}, year={2014}, month={Jan}, pages={69–80} }
 @article{babin_wang_rose_sagui_2013, title={Binding Polymorphism in the DNA Bound State of the Pdx1 Homeodomain}, volume={9}, ISSN={["1553-7358"]}, DOI={10.1371/journal.pcbi.1003160}, abstractNote={The subtle effects of DNA-protein recognition are illustrated in the homeodomain fold. This is one of several small DNA binding motifs that, in spite of limited DNA binding specificity, adopts crucial, specific roles when incorporated in a transcription factor. The homeodomain is composed of a 3-helix domain and a mobile N-terminal arm. Helix 3 (the recognition helix) interacts with the DNA bases through the major groove, while the N-terminal arm becomes ordered upon binding a specific sequence through the minor groove. Although many structural studies have characterized the DNA binding properties of homeodomains, the factors behind the binding specificity are still difficult to elucidate. A crystal structure of the Pdx1 homeodomain bound to DNA (PDB 2H1K) obtained previously in our lab shows two complexes with differences in the conformation of the N-terminal arm, major groove contacts, and backbone contacts, raising new questions about the DNA recognition process by homeodomains. Here, we carry out fully atomistic Molecular Dynamics simulations both in crystal and aqueous environments in order to elucidate the nature of the difference in binding contacts. The crystal simulations reproduce the X-ray experimental structures well. In the absence of crystal packing constraints, the differences between the two complexes increase during the solution simulations. Thus, the conformational differences are not an artifact of crystal packing. In solution, the homeodomain with a disordered N-terminal arm repositions to a partially specific orientation. Both the crystal and aqueous simulations support the existence of different stable binding conformers identified in the original crystallographic data with different degrees of specificity. We propose that protein-protein and protein-DNA interactions favor a subset of the possible conformations. This flexibility in DNA binding may facilitate multiple functions for the same transcription factor.}, number={8}, journal={PLOS COMPUTATIONAL BIOLOGY}, author={Babin, Volodymyr and Wang, Dongli and Rose, Robert B. and Sagui, Celeste}, year={2013}, month={Aug} }
 @article{moradi_babin_roland_sagui_2013, title={Reaction path ensemble of the B-Z-DNA transition: a comprehensive atomistic study}, volume={41}, ISSN={["1362-4962"]}, DOI={10.1093/nar/gks1003}, abstractNote={Since its discovery in 1979, left-handed Z-DNA has evolved from an in vitro curiosity to a challenging DNA structure with crucial roles in gene expression, regulation and recombination. A fundamental question that has puzzled researchers for decades is how the transition from B-DNA, the prevalent right-handed form of DNA, to Z-DNA is accomplished. Due to the complexity of the B–Z-DNA transition, experimental and computational studies have resulted in several different, apparently contradictory models. Here, we use molecular dynamics simulations coupled with state-of-the-art enhanced sampling techniques operating through non-conventional reaction coordinates, to investigate the B–Z-DNA transition at the atomic level. Our results show a complex free energy landscape, where several phenomena such as over-stretching, unpeeling, base pair extrusion and base pair flipping are observed resulting in interconversions between different DNA conformations such as B-DNA, Z-DNA and S-DNA. In particular, different minimum free energy paths allow for the coexistence of different mechanisms (such as zipper and stretch–collapse mechanisms) that previously had been proposed as independent, disconnected models. We find that the B–Z-DNA transition—in absence of other molecular partners—can encompass more than one mechanism of comparable free energy, and is therefore better described in terms of a reaction path ensemble.}, number={1}, journal={NUCLEIC ACIDS RESEARCH}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2013}, month={Jan}, pages={33–43} }
 @article{moradi_babin_sagui_roland_2011, title={A Statistical Analysis of the PPII Propensity of Amino Acid Guests in Proline-Rich Peptides}, volume={100}, ISSN={0006-3495}, url={http://dx.doi.org/10.1016/j.bpj.2010.12.3742}, DOI={10.1016/j.bpj.2010.12.3742}, abstractNote={There has been considerable debate about the intrinsic PPII propensity of amino-acid residues in denatured polypeptides. Experimentally, the propensity scale is based on the behavior of guest amino-acid residues placed in the middle of polyproline hosts. We have used classical molecular dynamics simulations, with state-of-the-art force fields to carry out a comprehensive analysis of the conformational equilibria of the proline-based host oligopeptides with single guests. The tracked structural characteristics include the PPII content, the cis/trans isomerization of the prolyl bonds, the puckering of the pyrrolidine rings of the proline residues, and the secondary structural motifs. We find no evidence for an intrinsic PPII propensity in any of the guest amino acids other than proline. Instead, the PPII content as derived from experiments may be explained in terms of: 1), a local correlation between the dihedral angles of the guest amino acid and the proline residue immediately preceding it; and 2), a nonlocal correlation between the cis/trans states of the peptide bonds. In terms of the latter, we find that the presence of a guest (other than proline, tyrosine, or tryptophan) increases the trans content of most of the prolyl bonds, which results in an effective increase of the peptide PPII content. With respect to the local dihedral correlations, we find that these are well described in terms of the so-called odds-ratio statistic. Expressed in terms of free energy language, the PPII content based on the odds-ratio of the relevant residues correlate well with the experimentally measured PPII content.}, number={4}, journal={Biophysical Journal}, publisher={Elsevier BV}, author={Moradi, Mahmoud and Babin, Volodymyr and Sagui, Celeste and Roland, Christopher}, year={2011}, month={Feb}, pages={1083–1093} }
 @article{moradi_sagui_roland_2011, title={Calculating relative transition rates with driven nonequilibrium simulations}, volume={518}, ISSN={["1873-4448"]}, DOI={10.1016/j.cplett.2011.10.054}, abstractNote={A formalism is presented for investigating transition pathways and transition probabilities for rare events in complex systems. Specifically, we show how driven simulations may be used to calculate relative reaction rates between stable states by means of nonequilibrium work measurements. Our relation between equilibrium and nonequilibrium rates may further be optimized by means of bidirectional estimators. A simple proline system is used to numerically illustrate the results.}, journal={CHEMICAL PHYSICS LETTERS}, author={Moradi, Mahmoud and Sagui, Celeste and Roland, Christopher}, year={2011}, month={Dec}, pages={109–113} }
 @article{moradi_babin_sagui_roland_2011, title={PPII Propensity of Multiple-Guest Amino Acids in a Proline-Rich Environment}, volume={115}, ISSN={1520-6106 1520-5207}, url={http://dx.doi.org/10.1021/jp203874f}, DOI={10.1021/jp203874f}, abstractNote={There has been considerable debate about the intrinsic PPII propensity of amino acid residues in denatured polypeptides. Experimentally, this scale is based on the behavior of guest amino acid residues placed in the middle of proline-based hosts. We have used classical molecular dynamics simulations combined with replica-exchange methods to carry out a comprehensive analysis of the conformational equilibria of proline-based host oligopeptides with multiple guest amino acids including alanine, glutamine, valine, and asparagine. The tracked structural characteristics include the secondary structural motifs based on the Ramachandran angles and the cis/trans isomerization of the prolyl bonds. In agreement with our recent study of single amino acid guests, we did not observe an intrinsic PPII propensity in any of the guest amino acids in a multiple-guest setting. Instead, the experimental results can be explained in terms of (i) the steric restrictions imposed on the C-terminal guest amino acid that is immediately followed by a proline residue and (ii) an increase in the trans content of the prolyl bonds due to the presence of guest residues. In terms of the latter, we found that the more guests added to the system, the larger the increase in the trans content of the prolyl bonds, which results in an effective increase in the PPII content of the peptide.}, number={26}, journal={The Journal of Physical Chemistry B}, publisher={American Chemical Society (ACS)}, author={Moradi, Mahmoud and Babin, Volodymyr and Sagui, Celeste and Roland, Christopher}, year={2011}, month={Jul}, pages={8645–8656} }
 @article{babin_roland_sagui_2011, title={The α-sheet: A missing-in-action secondary structure?}, volume={79}, ISSN={0887-3585}, url={http://dx.doi.org/10.1002/prot.22935}, DOI={10.1002/prot.22935}, abstractNote={Abstract}, number={3}, journal={Proteins: Structure, Function, and Bioinformatics}, publisher={Wiley}, author={Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2011}, month={Jan}, pages={937–946} }
 @article{moradi_babin_roland_sagui_2010, title={A classical molecular dynamics investigation of the free energy and structure of short polyproline conformers}, volume={133}, ISSN={["0021-9606"]}, DOI={10.1063/1.3481087}, abstractNote={Folded polyproline peptides can exist as either left-(PPII) or right-handed (PPI) helices, depending on their environment. In this work, we have characterized the conformations and the free energy landscapes of Ace–(Pro)n–Nme, n=2,3,…,9, and 13 peptides both in vacuo and in an implicit solvent environment. In order to enhance the sampling provided by regular molecular dynamics simulations, we have used the recently developed adaptively biased molecular dynamics method—which provides an accurate description of the free energy landscapes in terms of a set of relevant collective variables—combined with Hamiltonian and temperature replica exchange molecular dynamics methods. The collective variables, which are chosen so as to reflect the stable structures and the “slow modes” of the polyproline system, were based primarily on properties of length and of the cis/trans isomerization associated with the prolyl bonds. Results indicate that the space of peptide structures is characterized not just by pure PPII and PPI structures, but rather by a broad distribution of stable minima with similar free energies. These results are in agreement with recent experimental work. In addition, we have used steered molecular dynamics methods in order to quantitatively estimate the free energy difference of PPI and PPII for peptides of the length n=2,…,5 in vacuo and implicit water and qualitatively investigate transition pathways and mechanisms for the PPII to PPI transitions. A zipper-like mechanism, starting from either the center of the peptide or the amidated end, appear to be the most likely mechanisms for the PPII→PPI transition for the longer peptides.}, number={12}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2010}, month={Sep} }
 @article{babin_sagui_2010, title={Conformational free energies of methyl-alpha-L-iduronic and methyl-beta-D-glucuronic acids in water}, volume={132}, ISSN={["1089-7690"]}, DOI={10.1063/1.3355621}, abstractNote={We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a nonequilibrium umbrella sampling method, in this case, the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the weighted histogram analysis technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of α-L-iduronic acid and its C5 epimer β-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.}, number={10}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Babin, Volodymyr and Sagui, Celeste}, year={2010}, month={Mar} }
 @article{lee_sagui_roland_2010, title={Dimerization free energy of vancomycin-group antibiotics and the cooperative effect: A density functional approach}, volume={110}, ISSN={0020-7608}, url={http://dx.doi.org/10.1002/qua.22926}, DOI={10.1002/qua.22926}, abstractNote={Abstract}, number={15}, journal={International Journal of Quantum Chemistry}, publisher={Wiley}, author={Lee, Jung-Goo and Sagui, Celeste and Roland, Christopher}, year={2010}, month={Sep}, pages={2894–2902} }
 @article{moradi_lee_babin_roland_sagui_2010, title={Free energy and structure of polyproline peptides: An ab initio and classical molecular dynamics investigation}, volume={110}, ISSN={0020-7608}, url={http://dx.doi.org/10.1002/qua.22875}, DOI={10.1002/qua.22875}, abstractNote={Abstract}, number={15}, journal={International Journal of Quantum Chemistry}, publisher={Wiley}, author={Moradi, Mahmoud and Lee, Jung-Goo and Babin, Volodymyr and Roland, Christopher and Sagui, Celeste}, year={2010}, month={Aug}, pages={2865–2879} }
 @article{babin_karpusenka_moradi_roland_sagui_2009, title={Adaptively Biased Molecular Dynamics: An Umbrella Sampling Method With a Time-Dependent Potential}, volume={109}, ISSN={["1097-461X"]}, DOI={10.1002/qua.22413}, abstractNote={Abstract}, number={15}, journal={INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY}, author={Babin, Volodymyr and Karpusenka, Vadzim and Moradi, Mahmoud and Roland, Christopher and Sagui, Celeste}, year={2009}, month={Dec}, pages={3666–3678} }
 @article{moradi_babin_roland_darden_sagui_2009, title={Conformations and free energy landscapes of polyproline peptides}, volume={106}, ISSN={["0027-8424"]}, DOI={10.1073/pnas.0906500106}, abstractNote={The structure of the proline amino acid allows folded polyproline peptides to exist as both left- (PPII) and right-handed (PPI) helices. We have characterized the free energy landscapes of hexamer, nanomer, and tridecamer polyproline peptides in gas phase and implicit water as well as explicit hexane and 1-propanol for the nanomer. To enhance the sampling provided by regular molecular dynamics, we used the recently developed adaptively biased molecular dynamics method, which describes Landau free energy maps in terms of relevant collective variables. These maps, as a function of the collective variables of handedness, radius of gyration, and three others based on the peptide torsion angle ω, were used to determine the relative stability of the different structures, along with an estimate of the transition pathways connecting the different minima. Results show the existence of several metastable isomers and therefore provide a complementary view to experimental conclusions based on photo-induced electron transfer experiments with regard to the existence of stable heterogeneous subpopulations in PPII polyproline.}, number={49}, journal={PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}, author={Moradi, Mahmoud and Babin, Volodymyr and Roland, Christopher and Darden, Thomas A. and Sagui, Celeste}, year={2009}, month={Dec}, pages={20746–20751} }
 @article{babin_roland_sagui_2008, title={Adaptively biased molecular dynamics for free energy calculations}, volume={128}, DOI={10.1063/1.2844595}, abstractNote={We present an adaptively biased molecular dynamics (ABMD) method for the computation of the free energy surface of a reaction coordinate using nonequilibrium dynamics. The ABMD method belongs to the general category of umbrella sampling methods with an evolving biasing potential and is inspired by the metadynamics method. The ABMD method has several useful features, including a small number of control parameters and an O(t) numerical cost with molecular dynamics time t. The ABMD method naturally allows for extensions based on multiple walkers and replica exchange, where different replicas can have different temperatures and/or collective variables. This is beneficial not only in terms of the speed and accuracy of a calculation, but also in terms of the amount of useful information that may be obtained from a given simulation. The workings of the ABMD method are illustrated via a study of the folding of the Ace-GGPGGG-Nme peptide in a gaseous and solvated environment.}, number={13}, journal={Journal of Chemical Physics}, author={Babin, V. and Roland, C. and Sagui, C.}, year={2008} }
 @article{luo_qian_sagui_roland_2008, title={Amino acid adsorption on the Si(100) surface: The case of glycine}, volume={112}, ISSN={["1932-7455"]}, DOI={10.1021/jp0775193}, abstractNote={Using first principles total energy methods, we have investigated the adsorption of glycinethe simplest amino acidon the Si(100)- c(4 × 2)surface, with a focus on the associated energetics, charge transfer, electronic properties, and structural characteristics. We find that glycine adsorbs primarily on the “down” atoms of a Si dimer, with adsorption of the amino group being slightly favored over the absorption of the carboxylic acid group. Glycine on Si(100) may also involve the removal of a H atom from the chemical group most directly absorbed. In addition, there is evidence for a [2 + 2] cycloaddition reaction when both “CO” atoms absorb, as well as the more drastic breakup of the glycine molecule and the formation of a ketenimine molecule under high-energy conditions.}, number={7}, journal={JOURNAL OF PHYSICAL CHEMISTRY C}, author={Luo, Xuan and Qian, Gefei and Sagui, Celeste and Roland, Christopher}, year={2008}, month={Feb}, pages={2640–2648} }
 @article{karttunen_rottler_vattulainen_sagui_2008, title={Electrostatics in biomolecular simulations: Where are we now and where are we heading?}, volume={60}, ISBN={["978-0-12-373893-6"]}, ISSN={["1063-5823"]}, DOI={10.1016/s1063-5823(08)00002-1}, abstractNote={In this review, we discuss current methods and developments in the treatment of electrostatic interactions in biomolecular and soft matter simulations. We review the current ‘work horses’, namely, Ewald summation based methods such the Particle-Mesh Ewald, and others, and also newer real-space methods such as multigrid methods, and local algorithms for Coulomb's law. We also pay attention to boundary conditions. Although periodic boundary conditions are used most commonly, it is often desirable to have systems that are confined or have boundaries. Finally, we briefly describe some current and available software for the computation of electrostatics in biomolecular and soft matter simulations.}, journal={COMPUTATIONAL MODELING OF MEMBRANE BILAYERS}, author={Karttunen, Mikko and Rottler, Joerg and Vattulainen, Ilpo and Sagui, Celeste}, year={2008}, pages={49–89} }
 @article{odbadrakh_luo_lee_sagui_roland_2007, title={Theoretical investigation of the interaction of glycine with diamond C(100) and C(111) (2x1) surfaces}, volume={111}, ISSN={["1932-7455"]}, DOI={10.1021/jp073042j}, abstractNote={With density functional theory-based simulations, we have investigated the binding of the amino acid glycine on two of the most prominent diamond surfaces, that is, C(100) and C(111) (2 × 1), with a focus on the associated energetics, charge transfer, electronic, and structural characteristics. With regards to the dimerized C(100) surface, interaction is mostly via the amino group of the glycine molecule (both with and without H-atom abstraction) or the hydroxyl group with the loss of an associated H-atom. Barriers for these and other reactions were estimated with quantum chemistry methods. In contrast, the C(111) (2 × 1) surface was found to be mostly inert with respect to interactions with the glycine molecule.}, number={34}, journal={JOURNAL OF PHYSICAL CHEMISTRY C}, author={Odbadrakh, Khorgolkhuu and Luo, Xuan and Lee, Jung-Goo and Sagui, Celeste and Roland, Christopher}, year={2007}, month={Aug}, pages={12760–12767} }
 @article{lee_asciutto_babin_sagui_darden_roland_2006, title={Deprotonation of solvated formic acid: Car-Parrinello and metadynamics simulations}, volume={110}, ISSN={["1520-5207"]}, DOI={10.1021/jp055809i}, abstractNote={The deprotonation of solvated formic acid was investigated theoretically with ab initio simulations. With the Car-Parrinello method, deprotonation and reprotonation by means of a proton wire were observed. The microscopics of these reactions were analyzed, and reveal the key role played by nearby water molecules in catalyzing the reactions. A constrained molecular dynamics calculation was carried out to estimate the dissociation free energy. Deprotonation of formic acid was further investigated with the recently developed metadynamics method using the formic acid oxygen coordination numbers as the collective variables. The determined free-energy landscape gives barriers similar to that obtained with the constrained free-energy calculation.}, number={5}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Lee, JG and Asciutto, E and Babin, V and Sagui, C and Darden, T and Roland, C}, year={2006}, month={Feb}, pages={2325–2331} }
 @article{babin_baucom_darden_sagui_2006, title={Molecular dynamics simulations of DNA with polarizable force fields: Convergence of an ideal B-DNA structure to the crystallographic structure}, volume={110}, ISSN={["1520-5207"]}, DOI={10.1021/jp061421r}, abstractNote={We have investigated to what extent molecular dynamics (MD) simulations can reproduce DNA sequence-specific features, given different electrostatic descriptions and different cell environments. For this purpose, we have carried out multiple unrestrained MD simulations of the DNA duplex d(CCAACGTTGG)2. With respect to the electrostatic descriptions, two different force fields are studied: a traditional description based on atomic point charges and a polarizable force field. With respect to the cell environment, the difference between crystal and solution environments is emphasized, as well as the structural importance of divalent ions. By imposing the correct experimental unit cell environment, an initial configuration with two ideal B-DNA duplexes in the unit cell is shown to converge to the crystallographic structure. This convergence is measured by the appearance of sequence-dependent features that very closely resemble the crystallographic ones as well as by the decay of the all-atom root-mean-squared coordinates deviations (RMSD) with respect to the crystallographic structure. Given the appropriate crystallographic constraints, this is the first example of multiple nanosecond molecular dynamics trajectory that shows an ideal B-DNA model converging to an experimental structure, with a significant decay of RMSD.}, number={23}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Babin, Volodymyr and Baucom, Jason and Darden, Thomas A. and Sagui, Celeste}, year={2006}, month={Jun}, pages={11571–11581} }
 @article{babin_baucom_darden_sagui_2006, title={Molecular dynamics simulations of polarizable DNA in crystal environment}, volume={106}, ISSN={0020-7608 1097-461X}, url={http://dx.doi.org/10.1002/qua.21152}, DOI={10.1002/qua.21152}, abstractNote={Abstract}, number={15}, journal={International Journal of Quantum Chemistry}, publisher={Wiley}, author={Babin, Volodymyr and Baucom, Jason and Darden, Thomas A. and Sagui, Celeste}, year={2006}, pages={3260–3269} }
 @article{babin_roland_darden_sagui_2006, title={The free energy landscape of small peptides as obtained from metadynamics with umbrella sampling corrections}, volume={125}, ISSN={["1089-7690"]}, DOI={10.1063/1.2393236}, abstractNote={There is considerable interest in developing methodologies for the accurate evaluation of free energies, especially in the context of biomolecular simulations. Here, we report on a reexamination of the recently developed metadynamics method, which is explicitly designed to probe “rare events” and areas of phase space that are typically difficult to access with a molecular dynamics simulation. Specifically, we show that the accuracy of the free energy landscape calculated with the metadynamics method may be considerably improved when combined with umbrella sampling techniques. As test cases, we have studied the folding free energy landscape of two prototypical peptides: Ace-(Gly)2-Pro-(Gly)3-Nme in vacuo and trialanine solvated by both implicit and explicit water. The method has been implemented in the classical biomolecular code AMBER and is to be distributed in the next scheduled release of the code.}, number={20}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Babin, Volodymyr and Roland, Christopher and Darden, Thomas A. and Sagui, Celeste}, year={2006}, month={Nov} }
 @article{asciutto_sagui_2005, title={Exploring intramolecular reactions in complex systems with metadynamics: The case of the malonate anions}, volume={109}, ISSN={["1089-5639"]}, DOI={10.1021/jp053428z}, abstractNote={We have determined the optimized structures, relative energies and intramolecular reactions for two anionic forms of malonic acid, anion malonate(-1) (HO(2)CCH(2)CO(2)(-)) and malonate(-2) ((-)O(2)CCH(2)CO(2)(-)). For this purpose we employed accurate quantum chemistry calculations using second-order Möller-Plesset perturbation theory and Density Functional Theory with an aug'-cc-p-VTZ basis set to determine the structures and energies, and a novel metadynamics method based on Car-Parrinello molecular dynamics for the thermal reactions. For both malonates, we found new isomers (keto and enol structures) characterized by CO(2) rotations and intramolecular proton transfers. These proton transfers characterize the keto-enol tautomerism that takes place both in the monoanion and dianion. In all cases, the keto tautomer is the more stable configuration. The metadynamics method allows the system to explore the potential energy surface in a few picoseconds, crossing activation barriers of 20-50 kcal/mol.}, number={34}, journal={JOURNAL OF PHYSICAL CHEMISTRY A}, author={Asciutto, E and Sagui, C}, year={2005}, month={Sep}, pages={7682–7687} }
 @article{sagui_asciutto_roland_2005, title={New and exotic self-organized patterns for modulated nanoscale systems}, volume={5}, ISSN={["1530-6992"]}, DOI={10.1021/nl048224t}, abstractNote={The self-assembled domain patterns of modulated systems are the result of competing short-range attractive and long-range repulsive interactions found in diverse physical and chemical systems. From an application point of view, there is considerable interest in these domain patterns, as they form templates suitable for the fabrication of nanostructures. In this work we have generated a variety of new and exotic patterns, which represent either metastable or glassy states. These patterns arise as a compromise between the required equilibrium modulation period and the strain resulting from topologically constrained trajectories in phase space that effectively preclude the equilibrium configuration.}, number={2}, journal={NANO LETTERS}, author={Sagui, C and Asciutto, E and Roland, C}, year={2005}, month={Feb}, pages={389–395} }
 @article{lee_sagui_roland_2005, title={Quantum simulations of the structure and binding of glycopeptide antibiotic aglycons to cell wall analogues}, volume={109}, ISSN={["1520-5207"]}, DOI={10.1021/jp0548117}, abstractNote={The recent rise of vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) has given new impetus to the study of the binding between glycopeptide antibiotics and bacterial cell wall termini. Here, we report on an extensive first principles investigation of the binding of vancomycin, avoparcin, teicoplanin, and ristocetin aglycons with dipetides, Ac-d-Ala-X, where X = d-Lac and d-Ser (characteristic of VREs) and X = d-Ala, Gly (characteristic of non-VREs), and a model "methylated d-Ala" CH(2)CH(CH(3))COO(-), in liquid as well as gas phase. The gas-phase ordering of the binding, from strongest to weakest, is Gly, d-Ala, d-Ser, CH(2)CH(CH(3))COO(-), and d-Lac. Calculations show that the order of the Gly and d-Ala binding is reversed in solution. The results are in good agreement with recent experimental findings.}, number={43}, journal={JOURNAL OF PHYSICAL CHEMISTRY B}, author={Lee, JG and Sagui, C and Roland, C}, year={2005}, month={Nov}, pages={20588–20596} }
 @article{asciutto_roland_sagui_2005, title={Self-assembled patterns and strain-induced instabilities for modulated systems}, volume={72}, ISSN={["1550-2376"]}, DOI={10.1103/physreve.72.021504}, abstractNote={The self-assembled domain patterns of modulated systems are characteristic of a wide variety of chemical and physical systems, and are the result of competing interactions. From a technological point of view, there is considerable interest in these domain patterns, as they form suitable templates for the fabrication of nanostructures. We have analyzed the domains and instabilities that form in modulated systems, and show that a large variety of patterns--based on long-lived metastable or glassy states--may be formed as a compromise between the required equilibrium modulation period and the strain present in the system. The strain results from topologically constrained trajectories in phase space, that effectively preclude the equilibrium configuration.}, number={2}, journal={PHYSICAL REVIEW E}, author={Asciutto, E and Roland, C and Sagui, C}, year={2005}, month={Aug} }
 @article{herce_perera_darden_sagui_2005, title={Surface solvation for an ion in a water cluster}, volume={122}, ISSN={["0021-9606"]}, DOI={10.1063/1.1829635}, abstractNote={We have used molecular dynamics simulations to study the structural, dynamical, and thermodynamical properties of ions in water clusters. Careful evaluations of the free energy, internal energy, and entropy are used to address controversial or unresolved issues, related to the underlying physical cause of surface solvation, and the basic assumptions that go with it. Our main conclusions are the following. (i) The main cause of surface solvation of a single ion in a water cluster is both water and ion polarization, coupled to the charge and size of the ion. Interestingly, the total energy of the ion increases near the cluster surface, while the total energy of water decreases. Also, our analysis clearly shows that the cause of surface solvation is not the size of the total water dipole (unless this is too small). (ii) The entropic contribution is the same order of magnitude as the energetic contribution, and therefore cannot be neglected for quantitative results. (iii) A pure energetic analysis can give a qualitative description of the ion position at room temperature. (iv) We have observed surface solvation of a large positive iodinelike ion in a polarizable water cluster, but not in a nonpolarizable water cluster.}, number={2}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Herce, DH and Perera, L and Darden, TA and Sagui, C}, year={2005}, month={Jan} }
 @article{sagui_pomorski_darden_roland_2004, title={Ab initio calculation of electrostatic multipoles with Wannier functions for large-scale biomolecular simulations}, volume={120}, ISSN={["1089-7690"]}, DOI={10.1063/1.1644800}, abstractNote={It has long been known that accurate electrostatics is a key issue for improving current force fields for large-scale biomolecular simulations. Typically, this calls for an improved and more accurate description of the molecular electrostatic potential, which eliminates the artifacts associated with current point charge-based descriptions. In turn, this involves the partitioning of the extended molecular charge distribution, so that charges and multipole moments can be assigned to different atoms. As an alternate to current approaches, we have investigated a charge partitioning scheme that is based on the maximally localized Wannier functions. This has the advantage of partitioning the charge, and placing it around the molecule in a chemically meaningful manner. Moreover, higher order multipoles may all be calculated without any undue numerical difficulties. Tests on isolated molecules and water dimers, show that the molecular electrostatic potentials generated by such a Wannier-function based approach are in excellent agreement with the density functional-based calculations.}, number={9}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Sagui, C and Pomorski, P and Darden, TA and Roland, C}, year={2004}, month={Mar}, pages={4530–4544} }
 @article{lee_sagui_roland_2004, title={First principles investigation of vancomycin and teicoplanin binding to bacterial cell wall termini}, volume={126}, ISSN={["0002-7863"]}, DOI={10.1021/ja048645c}, abstractNote={The recent rise of vancomycin-resistant enterococci (VRE) has given new impetus to the study of the binding between glycopeptide antibiotics and bacterial cell wall termini. Here, we report on an extensive first principles investigation of the binding of vancomycin and teicoplanin with d-Ala-d-Lac (characteristic of VREs) and d-Ala-d-Ala (characteristic of non-VREs). Binding of both antibiotics to d-Ala-d-Ala was found to be stronger by about 3-5 kcal/mol and due primarily to the oxygen-oxygen lone-pair repulsion characteristic of the antibiotic/d-Ala-d-Lac complex. These results are in good agreement with recent experimental findings.}, number={27}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Lee, JG and Sagui, C and Roland, C}, year={2004}, month={Jul}, pages={8384–8385} }
 @article{baucom_transue_fuentes-cabrera_krahn_darden_sagui_2004, title={Molecular dynamics simulations of the d(CCAACGTTGG)(2) decamer in crystal environment: Comparison of atomic point-charge, extra-point, and polarizable force fields}, volume={121}, ISSN={["1089-7690"]}, DOI={10.1063/1.1788631}, abstractNote={Molecular dynamics simulations of the DNA duplex d(CCAACGTTGG)2 were used to study the relationship between DNA sequence and structure in a crystal environment. Three different force fields were used: a traditional description based on atomic point charges, a polarizable force field, and an “extra-point” force field (with additional charges on extranuclear sites). It is found that all the force fields reproduce fairly well the sequence-dependent features of the experimental structure. The polarizable force field, however, provides the most accurate representation of the crystal structure and the sequence-dependent effects observed in the experiment. These results point out to the need of the inclusion of polarization for accurate descriptions of DNA.}, number={14}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Baucom, J and Transue, T and Fuentes-Cabrera, M and Krahn, JM and Darden, TA and Sagui, C}, year={2004}, month={Oct}, pages={6998–7008} }
 @article{sagui_pedersen_darden_2004, title={Towards an accurate representation of electrostatics in classical force fields: Efficient implementation of multipolar interactions in biomolecular simulations}, volume={120}, ISSN={["1089-7690"]}, DOI={10.1063/1.1630791}, abstractNote={The accurate simulation of biologically active macromolecules faces serious limitations that originate in the treatment of electrostatics in the empirical force fields. The current use of “partial charges” is a significant source of errors, since these vary widely with different conformations. By contrast, the molecular electrostatic potential (MEP) obtained through the use of a distributed multipole moment description, has been shown to converge to the quantum MEP outside the van der Waals surface, when higher order multipoles are used. However, in spite of the considerable improvement to the representation of the electronic cloud, higher order multipoles are not part of current classical biomolecular force fields due to the excessive computational cost. In this paper we present an efficient formalism for the treatment of higher order multipoles in Cartesian tensor formalism. The Ewald “direct sum” is evaluated through a McMurchie–Davidson formalism [L. McMurchie and E. Davidson, J. Comput. Phys. 26, 218 (1978)]. The “reciprocal sum” has been implemented in three different ways: using an Ewald scheme, a particle mesh Ewald (PME) method, and a multigrid-based approach. We find that even though the use of the McMurchie–Davidson formalism considerably reduces the cost of the calculation with respect to the standard matrix implementation of multipole interactions, the calculation in direct space remains expensive. When most of the calculation is moved to reciprocal space via the PME method, the cost of a calculation where all multipolar interactions (up to hexadecapole–hexadecapole) are included is only about 8.5 times more expensive than a regular AMBER 7 [D. A. Pearlman et al., Comput. Phys. Commun. 91, 1 (1995)] implementation with only charge-charge interactions. The multigrid implementation is slower but shows very promising results for parallelization. It provides a natural way to interface with continuous, Gaussian-based electrostatics in the future. It is hoped that this new formalism will facilitate the systematic implementation of higher order multipoles in classical biomolecular force fields.}, number={1}, journal={JOURNAL OF CHEMICAL PHYSICS}, author={Sagui, C and Pedersen, LG and Darden, TA}, year={2004}, month={Jan}, pages={73–87} }
 @article{herce_darden_sagui_2003, title={Calculation of ionic charging free energies in simulation systems with atomic charges, dipoles, and quadrupoles}, volume={119}, DOI={10.1063/1.1609191}, abstractNote={The ionic charging free energy is a very sensitive probe for the treatment of electrostatics in any given simulation setting. In this work, we present methods to compute the ionic charging free energy in systems characterized by atomic charges and higher-order multipoles, mainly dipoles and quadrupoles. The results of these methods for periodic boundary conditions and for spherical clusters are then compared. For the treatment of spherical clusters, we introduce a generalization of Gauss’ law that links the microscopic variables to the measurable macroscopic electrostatics via a work function.}, number={15}, journal={Journal of Chemical Physics}, author={Herce, H. D. and Darden, T. and Sagui, C.}, year={2003}, pages={7621–7632} }
 @article{somoza_sagui_roland_2001, title={Liquid-crystal phases of capped carbon nanotubes}, volume={63}, ISSN={["1550-235X"]}, DOI={10.1103/physrevb.63.081403}, abstractNote={sociated with the electronic properties of carbon nanotubes. Depending on their helicity, single-wall nanotubes are either metallic or semiconducting, and therefore have the potential of forming the basis of a future all-carbon, nanotube-based microelectronics. 2 It is also clear that finite-sized carbon nanotubes are variable-length rods, which by virtue of their shape and size can act as liquid crystals. 3 To examine the possibility of nanotubes forming tailored liquid crystals for application purposes, we investigated the phase diagrams of capped nanotubes as a function of nanotube length and diameter in two limits: in the presence of the attractive van der Waals forces, and in the hard-rod limit characteristic of nanotubes in which such interactions are completely screened. Our results show that when attractive interactions are present, the columnar phase preempts all others at room temperatures.}, number={8}, journal={PHYSICAL REVIEW B}, author={Somoza, AM and Sagui, C and Roland, C}, year={2001}, month={Feb} }