@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{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} }
 @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={Alzheimer's disease is linked to the aggregation of the amyloid-β protein (Aβ) of 40 or 42 amino acids. Lipid membranes are known to modulate the rate and mechanisms of the Aβ aggregation. Point mutations in Aβ can alter these rates and mechanisms. In particular, experiments show that F19 mutations influence the aggregation rate, but maintain the fibril structures. Here, we used molecular dynamics simulations to examine the effect of the F19W mutation in the 3Aβ11–40 trimer immersed in DPPC lipid bilayers submerged in aqueous solution. Substituting Phe by its closest (non-polar) aromatic amino acid Trp has a dramatic reduction in binding affinity to the phospholipid membrane (measured with respect to the solvated protein) compared to the wild type: the binding free energy of the protein–DPPC lipid bilayer increases by 40–50 kcal mol−1 over the wild-type. This is accompanied by conformational changes and loss of salt bridges, as well as a more complex free energy surface, all indicative of a more flexible and less stable mutated trimer. These results suggest that the impact of mutations can be assessed, at least partially, by evaluating the interaction of the mutated peptides with the lipid membranes.}, 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 Expansion of the GAA/TTC repeats in the first intron of the FXN gene causes Friedreich’s ataxia. Non-canonical structures are linked to this expansion. DNA triplexes and R-loops are believed to arrest transcription, which results in frataxin deficiency and eventual neurodegeneration. We present a systematic in silico characterization of the possible DNA triplexes that could be assembled with GAA and TTC strands; the two hybrid duplexes [r(GAA):d(TTC) and d(GAA):r(UUC)] in an R-loop; and three hybrid triplexes that could form during bidirectional transcription when the non-template DNA strand bonds with the hybrid duplex (collapsed R-loops, where the two DNA strands remain antiparallel). For both Y·R:Y and R·R:Y DNA triplexes, the parallel third strand orientation is more stable; both parallel and antiparallel protonated d(GA+A)·d(GAA):d(TTC) triplexes are stable. Apparent contradictions in the literature about the R·R:Y triplex stability is probably due to lack of molecular resolution, since shifting the third strand by a single nucleotide alters the stability ranking. In the collapsed R-loops, antiparallel d(TTC+)·d(GAA):r(UUC) is unstable, while parallel d(GAA)·r(GAA):d(TTC) and d(GA+A)·r(GAA):d(TTC) are stable. In addition to providing new structural perspectives for specific therapeutic aims, our results contribute to a systematic structural basis for the emerging field of quantitative R-loop biology.}, 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_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{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{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} }