@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{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{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} }