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

Abstract

Solution state x-ray diffraction fingerprinting is demonstrated as a method for experimentally assessing the accuracy of molecular dynamics (MD) simulations. Fourier transforms of coordinate data from MD simulations are used to produce reciprocal space ''fingerprints'' of atomic pair distance correlations that are characteristic of the ensemble and are the direct numerical analogues of experimental solution x-ray diffraction (SXD). SXD experiments and MD simulations were carried out to test the ability of experiment and simulation to resolve sequence-dependent modifications in helix conformation for B-form DNA. SXD experiments demonstrated that solution-state poly(AT) and poly(A)-poly(T) duplex DNA sequences exist in ensembles close to canonical B-form and B -form structures, respectively. In contrast, MD simulations analyzed in terms of SXD fingerprints are shown to deviate from experiment, most significantly for poly(A)-poly(T) duplex DNA. Compared with experiment, MD simulation shortcomings were found to include both mismatches in simulated conformer structures and number population within the ensembles. This work demonstrates an experimental approach for quantitatively evaluating MD simulations and other coordinate models to simulate biopolymer structure in solution and suggests opportunities to use solution diffraction data as experimental benchmarks for developing supramolecular force fields optimized for a range of in situ applications. solution x-ray scattering ͉ wide-angle x-ray scattering ͉ A-tract DNA ͉ structural landscape C haracterization of the structure and dynamics of biological macromolecules in liquids and other physiologically relevant noncrystalline media is critical for achieving a full understanding of chemical and biological function at the molecular level (1, 2). 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 (3-5). 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.A general problem for the evaluation of MD simulation is the lack of a sufficient experimental database on solution-state DNA structure. Crystal-packing distortions of DNA and the intrinsic lack of long-range structural data from NMR measurements restricts the reliable database on DNA structure to local structural parameters (7,8). It is an open question whether force fields focused primarily on local structure parameters are sufficient to accurately model the full range of DNA conformational landscapes in solution.Recently, a number of reports have shown that wide-angle x-ray scattering provides a direct measure of macromolecular conforma...

Spermine Condenses DNA, but Not RNA Duplexes

“…This is in agreement with previous work that compared MD simulations of nucleic acids with WAXS data (54,55). Our model of spermine association to DNA is consistent with NMR studies, which suggest either that the spermine diffuses rapidly along the DNA molecule or that there are not discrete binding sites (56), and with the conclusions of Raman spectroscopy studies that also support non-specific electrostatic binding (57).…”

A Physical Picture of Atomic Motions within the Dickerson DNA Dodecamer in Solution Derived from Joint Ensemble Refinement against NMR and Large-Angle X-ray Scattering Data

“…Unlike the case of small-angle scattering, the parametrization of I q (through f eff ) for large-angle scattering is lower in quality such that quantitative agreement of peak intensity is not achieved (28,29). Peak positions do seem to be reproduced well by eq 8 using the current parametrization.…”

Fluorescence of the DNA Double Helix (dA)20·(dT)20 Studied by Femtosecond SpectroscopyEffect of the Duplex Size on the Properties of the Excited States

“…(dAdT) 9 by transient absorption with femtosecond resolution. 15 The time constant of 150 ps, corresponding to an important part of the signal determined for (dA) 18 . (dT) 18 by transient absorption, is about two orders of magnitude larger than that observed for (dA) 20 .…”

“…15 The time constant of 150 ps, corresponding to an important part of the signal determined for (dA) 18 . (dT) 18 by transient absorption, is about two orders of magnitude larger than that observed for (dA) 20 . (dT) 20 by fluorescence upconversion (1.23 ps).…”

“…Buchvarov et al, 17 found indeed a weak difference between (dA) 12 . (dT) 12 and (dA) 18 . (dT) 18 .…”