Molecular Dynamics Simulations on the Hydration, Structure and Motions of DNA Oligomers

Beveridge, D. L.; Swaminathan, S.; Ravishanker, G.; Withka, Jane M.; Srinivasan, Jayashree; Prévost, Chantal; Louise‐May, Shirley; Langley, David R.; DiCapua, Frank M.; Bolton, Philip H.

doi:10.1007/978-1-349-12359-9_6

Cited by 53 publications

(40 citation statements)

References 169 publications

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“…150 -152 Status reports on nucleic acid force fields were recently provided by Cheatham and Young 153 and MacKerell et al 154 This laboratory has also contributed reviews on the special topics of DNA hydration, 150 the ion atmosphere of DNA, 155 and protein-DNA interactions. 156 Notable independent reviews of MD on DNA are due to Cheatham and Kollman, 157 Giudice and Lavery, 158 Norberg and Nilsson, 159 and Orozco et al 160 In this laboratory, extensive MD simulations on the oligonucleotide d(CGCGAATTCGCG) as a prototype case have been carried out.…”

Section: Models Of Dna Structure In Solutionmentioning

confidence: 95%

Molecular dynamics simulations of DNA curvature and flexibility: Helix phasing and premelting

et al. 2004

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Recent studies of DNA axis curvature and flexibility based on molecular dynamics (MD) simulations on DNA are reviewed. The MD simulations are on DNA sequences up to 25 base pairs in length, including explicit consideration of counterions and waters in the computational model. MD studies are described for ApA steps, A-tracts, for sequences of A-tracts with helix phasing. In MD modeling, ApA steps and A-tracts in aqueous solution are essentially straight, relatively rigid, and exhibit the characteristic features associated with the B'-form of DNA. The results of MD modeling of A-tract oligonucleotides are validated by close accord with corresponding crystal structure results and nuclear magnetic resonance (NMR) nuclear Overhauser effect (NOE) and residual dipolar coupling (RDC) structures of d(CGCGAATTCGCG) and d(GGCAAAAAACGG). MD simulation successfully accounts for enhanced axis curvature in a set of three sequences with phased A-tracts studied to date. The primary origin of the axis curvature in the MD model is found at those pyrimidine/purine YpR "flexible hinge points" in a high roll, open hinge conformational substate. In the MD model of axis curvature in a DNA sequence with both phased A-tracts and YpR steps, the A-tracts appear to act as positioning elements that make the helix phasing more precise, and key YpR steps in the open hinge state serve as curvature elements. Our simulations on a phased A-tract sequence as a function of temperature show that the MD simulations exhibit a premelting transition in close accord with experiment, and predict that the mechanism involves a B'-to-B transition within A-tracts coupled with the prediction of a transition in key YpR steps from the high roll, open hinge, to a low roll, closed hinge substate. Diverse experimental observations on DNA curvature phenomena are examined in light of the MD model with no serious discrepancies. The collected MD results provide independent support for the "non-A-tract model" of DNA curvature. The "junction model" is indicated to be a special case of the non-A-tract model when there is a Y base at the 5' end of an A-tract. In accord with crystallography, the "ApA wedge model" is not supported by MD.

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Section: Models Of Dna Structure In Solutionmentioning

confidence: 95%

Molecular dynamics simulations of DNA curvature and flexibility: Helix phasing and premelting

et al. 2004

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“…Computer simulations of explicit solvent allow the calculation of water density distributions around DNA, 26,87 complementing the crystallographic results. The locations with the highest water densities can be easily compared with experimental hydration sites to establish confidence in the theoretical methods while additional information about the distribution of less ordered water molecules is available from the simulation beyond experimental resolution.…”

Section: Structure Of Dna Hydrationmentioning

confidence: 99%

A molecular simulation picture of DNA hydration around A- and B-DNA

1998

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“…Although computationally quite intensive, MD can generate all-atom description of the dynamics of in vitro DNA oligonucleotides in solution including solvent water and counterions explicitly, and the structural characteristics of DNA suitable for this project can be obtained from an analysis of MD results. The field of MD applied to DNA and nucleic acids in general has been under serious development since the early 1980s (30). The assessments of current MD force fields and simulation protocols compared with experimental data show dramatic improvement in recent years (3,4).…”

Section: Introductionmentioning

confidence: 99%

Hidden Markov models from molecular dynamics simulations on DNA

Thayer

Beveridge

2002

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

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An enhanced bioinformatics tool incorporating the participation of molecular structure as well as sequence in protein DNA recognition is proposed and tested. Boltzmann probability models of sequencedependent DNA structure from all-atom molecular dynamics simulations were obtained and incorporated into hidden Markov models (HMMs) that can recognize molecular structural signals as well as sequence in protein-DNA binding sites on a genome. The binding of catabolite activator protein (CAP) to cognate DNA sequences was used as a prototype case for implementation and testing of the method. The results indicate that even HMMs based on probabilistic roll͞tilt dinucleotide models of sequence-dependent DNA structure have some capability to discriminate between known CAP binding and nonbinding sites and to predict putative CAP binding sites in unknowns. Restricting HMMs to sequence only in regions of strong consensus in which the protein makes base specific contacts with the cognate DNA further improved the discriminatory capabilities of the HMMs. Comparison of results with controls based on sequence only indicates that extending the definition of consensus from sequence to structure improves the transferability of the HMMs, and provides further supportive evidence of a role for dynamical molecular structure as well as sequence in genomic regulatory mechanisms. T he idea that structure as well as sequence might serve as a useful bioinformatics screening criterion has considerable potential in genomics for elucidating similarities with low sequence consensus. The proposal that protein-DNA recognition involves molecular geometry as a supplement to sequence-based, nonbonded contacts dates back at least to the observation of structural irregularities in the first high-resolution x-ray crystal structure of B-DNA (1, 2). However, structural characteristics of DNA at the most fundamental level, Boltzmann statistical mechanics, is described in terms of the probability of achieving a particular conformational or helicoidal state at a given temperature, rather than a single time averaged form. We propose herein a methodology in which probability models of dynamical structure derived from molecular dynamics (MD) simulations on DNA including counterions and water (3, 4) are incorporated along with DNA sequence information into hidden Markov models (HMM) (5, 6) suitable for genomic analysis. HMMs already provide a statistical framework for protein and DNA sequence alignments (6-8), and the probabilistic nature of HMMs per se (9, 10) is ideally suited for incorporating Boltzmann probability models of molecular structural characteristics from MD into a bioinformatics tool. The binding of catabolite activator protein (CAP) to cognate DNA sequences (11-13) serves as a model protein-DNA binding system and basis for demonstration and testing of the methodology. The resulting HMMs are applied to scans of the Escherichia coli genome. The results provide further exploration of a role for molecular geometry as well as sequence in protein DNA rec...

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Molecular Dynamics Simulations on the Hydration, Structure and Motions of DNA Oligomers

Cited by 53 publications

References 169 publications

Molecular dynamics simulations of DNA curvature and flexibility: Helix phasing and premelting

Molecular dynamics simulations of DNA curvature and flexibility: Helix phasing and premelting

A molecular simulation picture of DNA hydration around A- and B-DNA

Hidden Markov models from molecular dynamics simulations on DNA

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