Molecular dynamics simulations of an oligonucleotide duplex with adenine tracts phased by a full helix turn 1 1Edited by B. Honig

Young, Matthew A.; Beveridge, D. L.

doi:10.1006/jmbi.1998.1962

Cited by 123 publications

(121 citation statements)

References 67 publications

(70 reference statements)

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“…Following recent advances in methodology and computational power, 42 it is now possible to simulate nucleic acid fragments in explicit solvent over many nanoseconds. [43][44][45][46][47][48][49] At the same time the nucleic acid and solvent structures remain close to experimentally expected conformations, 43,47,50 lending support to the general validity of the theoretical models. However, closer inspection of the influence of different force fields have revealed biases toward A-or B-form conformations.…”

Section: Introductionmentioning

confidence: 50%

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

1998

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Section: Introductionmentioning

confidence: 50%

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

1998

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“…The assessments of current MD force fields and simulation protocols compared with experimental data show dramatic improvement in recent years (3,4). Although some specific deficiencies remain, successful descriptions of DNA sequence effects on dynamical structure (31,32), conformational transitions (33,34), and salient features of DNA bending and bendability (35)(36)(37) have been reported. However, to our knowledge, MD on DNA has not heretofore served as the basis for a genomic search.…”

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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“…In general, DNA sequences comply with this requirement, being supple, flexible, and deformable. A conspicuous exception is provided by runs of successive adenine bases, or A-tracts, which are characterized by an unusual rigidity and hence an exceptional aversion toward conformational changes (15)(16)(17)(18)(19)(20). The distinctive structural features of A-tracts and the potential effects of these features upon DNAprotein interactions prompted us to examine the susceptibility of this motif to contextual effects.…”

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confidence: 99%

Contextual Equilibrium Effects in DNA Molecules

Goobes

Minsky

2001

Journal of Biological Chemistry

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The thermodynamic parameters of DNA triplex formation between oligonucleotides and double-stranded DNA segments containing adenine runs (A-tracts) were investigated to explore equilibrium structural effects exerted by flanking segments upon the A-tracts. Results obtained from isothermal titration calorimetry, temperature-dependent circular dichroism (CD), and UV melting experiments indicate that A-tracts, considered as a uniquely robust and inflexible DNA motif, can be structurally perturbed by neighboring sequences in a way that significantly affects the propensity of this motif to interact with triplex-forming oligonucleotides. These contextual equilibrium effects, which depend upon the composition and location of the flanking sequences, are likely to apply not only to the interaction of A-tracts with single-stranded DNA molecules but also to interactions with drugs and proteins. As such, the current results refine the guidelines for the design of triplexforming oligonucleotides used for antigene strategies. More generally, they substantiate the notion that significant data might be encoded by structural DNA parameters.The demonstrated in vivo existence of non-B-DNA morphologies and the potential involvement of such altered structures in the regulation and fine-tuning of cellular processes (1, 2) elicited intensive studies on the factors that affect and modulate DNA conformational transitions. It is well established that the physical chemistry of these transitions is determined by an intricate array of environmental conditions and intrinsic factors, including the ionic strength, relative humidity, pH, and torsional strain. The actual structure exhibited by a given DNA segment is, however, generally considered to be dictated by the particular composition and sequential order of the base pairs within this segment. Indeed, left-handed DNA conformations, cruciforms, intramolecular triplexes, as well as bent or macroscopically curved motifs are detected predominantly in nonrandom DNA sequences such as alternating purine-pyrimidine segments, direct or inverted repeats, and purine-rich tracts (2). Several studies have indicated, however, that the kinetics of a conformational change, as well as the features of the resulting DNA structure, may be influenced or even dominated by sequences that are removed from those directly participating in the transition.The first evidence that structural information can be transmitted along the DNA molecule was provided by the observation that the melting of a DNA segment can be strongly affected by the base composition of a contiguous region (3). The kinetics of cruciform extrusion (4), as well as of the formation of intramolecular triple-stranded DNA motifs (5), were found to be dominated by sequences flanking the region that undergoes the transition. The effects were shown to operate over relatively long distances and to be independent of polarity. Right-to-lefthanded transitions of alternating d(G-C) n and d(A-T) n segments were also found to be significantly modulated by regions...

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Molecular dynamics simulations of an oligonucleotide duplex with adenine tracts phased by a full helix turn 1 1Edited by B. Honig

Cited by 123 publications

References 67 publications

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

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

Hidden Markov models from molecular dynamics simulations on DNA

Contextual Equilibrium Effects in DNA Molecules

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