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

Abstract

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.

X-ray diffraction “fingerprinting” of DNA structure in solution for quantitative evaluation of molecular dynamics simulation

“…Although the currently available force fields for DNA have been found to be remarkably successful for simulating a broad range of sequence-dependent structural features (3)(4)(5), variances between simulations suggest a significant level of uncertainty in the prediction of structural details (4,6,(24)(25)(26). In the present work, we have extended these findings by using SXD measurements to provide indices for tabulating goodness-of-fit between experiment and coordinate models.…”

“…Molecular dynamics (MD) simulations based on molecular mechanical force fields and Ewald-type treatments for the long-range electrostatic interactions have been remarkably successful in simulating the general features of DNA sequence-dependent conformations, conformational transitions, and nucleic acid-drug interactions (3)(4)(5). However, variances in the details of simulated DNA structure based on choice of force fields and simulation conditions (4,6) suggest levels of uncertainty in the prediction of DNA structure that are likely to undermine attempts to understand function at the atomic scale.…”

Ion motions in molecular dynamics simulations on DNA

“…The ability to obtain an all-atom model of the DNA, water, and counterions from molecular simulation is of a much more recent vintage, and required force field development (19), new methodology (20), and access to the latest generation of research supercomputers. MD simulation has now been applied successfully to a number of DNA oligonucleotides in solution (13,14,(21)(22)(23). In particular, close accord between MD results and observed NMR NOESY peak volumes and structures obtained for d(CGC-GAATTCGCG) 2 , with the addition of residual dipolar couplings, has been established (24).…”

“…This finding is consistent with the ideas of Hud and Plavec (5) for sequence-directed curvature in which A-tract DNA, which by their definition includes the AATT sequence, localizes ions into the minor groove at positions close to those found in the MD. However, cause and effect with respect to ions and DNA deformations and axis curvature remain to be established with certainty (23).…”

On the Relationship between DNA Periodicity and Local Chromatin Structure

“…These ∼10 bp periodicities are strongly correlated with nucleosome positioning, supporting the hypothesis that periodic sequence elements in phase with the DNA helix are related to large-scale bending of the DNA molecule. DNA bendability has been extensively modeled [10], [11], [12], and experimentally measured [13], with a general consensus that poly(dA:dT) tracts are extremely stiff [14], while some short sequences are very flexible, particularly the CA/TG dinucleotide and the CAG/CTG trinucleotide [15], and others such as TA are context-dependent [10].…”