Conformational and Helicoidal Analysis of 30 PS of Molecular Dynamics on the d(CGCGAATTCGCG) Double Helix: “Curves”, Dials and Windows

Ravishanker, G.; Swaminathan, S.; Beveridge, D. L.; Lavery, Richard; Sklenar, Heinz

doi:10.1080/07391102.1989.10507729

Cited by 239 publications

(196 citation statements)

References 25 publications

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“…The extent of DNA bending for p53 core domain tetramer-DNA complexes Ho, Ho_CAAG, Ho_CTAG and Ho_CTTG from the 60 ns (A) and the 30 ns (B) trajectories. The DNA curvature was calculated with the CURVES program 35,50 . The starting structure difference between (A) and (B) was the one following the minimization steps in the preparation stage.…”

Section: Discussionmentioning

confidence: 99%

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

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Specific p53 binding-induced DNA bending and its underlying driving forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome. However, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half site, different DNA bending extents were observed. Our analysis shows that the interactions between p53 dimer-dimer were similar in all complexes; on the other hand, specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120 and Arg248 with the DNA varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence, and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory while those for the CTAG sequence was partially dissociated in part of the trajectory, which affected the stability of nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which in turn are related to the DNA sequence and DNA flexibility.

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Section: Discussionmentioning

confidence: 99%

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

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“…In Values of selected average helicoidal parameters, backbone angles, and sugar pucker values are presented for a canonical A-DNA model structure (canonical-A), the simulation of A-DNA in mixed ethanol͞water solution (A-DNA, 2,000-3,000 ps), the simulation of B-DNA with the modified V2 term on the O-C-C-O torsions (from 1.0 to 0.3 kcal͞mol), which underwent a B-DNA to A-DNA transition (A-DNAV2ϭ0.3, 2,000-3,000 ps), A-RNA in pure water (A-RNA, 1,030-2,030 ps) (23), and B-DNA in pure water (B-DNA, 400-1,400 ps) (16). All of the helicoidal values were calculated using the Dials and Windows interface (27) to Curves (28) from average structures over 1 ns portions of the trajectories (except in the case of the canonical A-DNA structure). The average structures were created by RMS fitting all DNA atoms at 1 ps intervals from the trajectories and coordinate averaging.…”

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confidence: 99%

A molecular level picture of the stabilization of A-DNA in mixed ethanol–water solutions

Cheatham

Crowley

Fox

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

107

126

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Advances in computer power, methodology, and empirical force fields now allow routine ''stable'' nanosecond-length molecular dynamics simulations of DNA in water. The accurate representation of environmental inf luences on structure remains a major, unresolved issue. In contrast to simulations of A-DNA in water (where an A-DNA to B-DNA transition is observed) and in pure ethanol (where disruption of the structure is observed), A-DNA in Ϸ85% ethanol solution remains in a canonical A-DNA geometry as expected. The stabilization of A-DNA by ethanol is likely due to disruption of the spine of hydration in the minor groove and the presence of ion-mediated interhelical bonds and extensive hydration across the major groove.

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“…Stacking interactions were estimated by computing the van der Waals interaction energies between adjacent base pairs, including the damaged base and partner pair, with the program ANAL of AMBER. DNA duplex groove dimensions and bend angles were computed with the MD Toolchest (53,54) and CURVES (53) programs, respectively. The solvent accessible surface area was computed using the Connolly algorithm (55) implemented in Insight II (Accelrys Inc.) with a probe radius of 1.4 Å.…”

Section: Methodsmentioning

confidence: 99%

Conformational Properties of Equilenin−DNA Adducts: Stereoisomer and Base Effects

Ding

Shapiro

Cai

et al. 2008

Chem. Res. Toxicol.

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Equilin and equilenin, components of the hormone replacement therapy drug Premarin, can be metabolized to the catechol 4-hydroxyequilenin (4-OHEN). The quinoids produced by 4-OHEN oxidation react with dC, dA and dG to form unusual stable cyclic adducts, which have been found in human breast tumor tissue. Four stereoisomeric adducts have been identified for each base. These twelve Premarin-derived adducts provide a unique opportunity for analyzing effects of stereochemistry and base damage on DNA structure, and consequently its function. Our computational studies have shown that these adducts, with obstructed Watson-Crick hydrogen bond edges and near-perpendicular ring systems, have limited conformational flexibility, and near-mirror image conformations in stereoisomer pairs. The dC and dA adducts can adopt major and minor groove positions in the double helix, but the dG adducts are positioned only in the major groove. In all cases, opposite orientations of the equilenin rings with respect to the 5'→3' direction of the damaged strand are found in stereoisomer pairs derived from the same base, and no Watson-Crick pairing is possible. However, detailed structural properties in DNA duplexes are distinct for each stereoisomer of each damaged base. These differences may underlie observed differential stereoisomer and basedependent mutagenicities and repair susceptibilities of these adducts.The hormone replacement drug Premarin, whose use has been shown to increase breast cancer risk (1-6), contains the equine estrogens equilin and equilenin ( Figure 1). This pair of substances can be metabolized to highly reactive 4-OHEN quinoids that can form unusual stable cyclic adducts with dC, dA and dG (7-9). There are four different stereoisomers for each base adduct (9-11), for a total of twelve distinct lesions (Figure 1). The structural properties of this set of twelve DNA adducts present a fascinating opportunity for elucidating how the stereochemical features and the nature of the damaged base differentially distort and destabilize the local structure of double-stranded DNA molecules around the lesion sites. Such differences *Corresponding author: Suse Broyde, tel. (212)998-8231, fax (212)995-4015, email broyde@nyu.edu. Supporting Information Available: Details of the molecular dynamics protocol of 4-OHEN-G adducts in duplexes are provided. Table S1 gives glycosidic torsion χ values of the modified guanine, box sizes and numbers of waters in the MD simulation starting models. Table S2 gives added force field parameters for the modified guanine. Table S3 gives AMBER atom type, connection type, and partial charge assignments for the 4-OHEN-G adducts. Table S4 gives MM-PBSA free energy components of the lowest free energy conformation for each 4-OHEN-G stereoisomer modified duplexes. Table S5 gives solvent accessible surfaces of the equilenin rings of 4-OHEN adducts in 11mer duplexes. Table S6 gives hydrogen bonds and occupancies at the lesion sites of 4-OHEN-G modified duplexes. Table S7 gives van der Waals interact...

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Conformational and Helicoidal Analysis of 30 PS of Molecular Dynamics on the d(CGCGAATTCGCG) Double Helix: “Curves”, Dials and Windows

Cited by 239 publications

References 25 publications

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

A molecular level picture of the stabilization of A-DNA in mixed ethanol–water solutions

Conformational Properties of Equilenin−DNA Adducts: Stereoisomer and Base Effects

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