Assessment of the molecular dynamics structure of DNA in solution based on calculated and observed NMR NOESY volumes and dihedral angles from scalar coupling constants

Arthanari, Haribabu; McConnell, Kevin J.; Beger, Richard D.; Young, Matthew A.; Beveridge, David L.; Bolton, Philip H.

doi:10.1002/bip.10263

Cited by 36 publications

(41 citation statements)

References 55 publications

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“…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.…”

Section: Resultsmentioning

confidence: 72%

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

Zuo

Cui

Merz

et al. 2006

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

109

137

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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...

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Section: Resultsmentioning

confidence: 72%

“…Prior experimental validation of MD simulation have compared crystallographic and NMR data (8,24,26,28,29). However, potential distortions of DNA conformation by crystal packing forces and the short-range nature of solution NMR interactions have largely limited the reliable experimental database to local structural parameters.…”

Section: Resultsmentioning

confidence: 99%

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

Zuo

Cui

Merz

et al. 2006

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

109

137

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“…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).…”

Section: Introductionmentioning

confidence: 77%

Ion motions in molecular dynamics simulations on DNA

Ponomarev

Thayer

Beveridge

2004

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

225

246

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Counterions play a significant role in DNA structure and function, and molecular dynamics (MD) simulations offer the prospect of detailed description of the dynamical structure of ions at the molecular level. However, the motions of mobile counterions are notably slow to converge in MD on DNA. Obtaining accurate and reliable MD simulations requires knowing just how much sampling is required for convergence of each of the properties of interest. To address this issue, MD on a d(CGCGAATTCGCG) duplex in a dilute aqueous solution of water and 22 Na ؉ counterions was performed until convergence was achieved. The calculated first shell ion occupancies and DNA-Na ؉ radial distribution functions were computed as a function of time to assess convergence, and compared with relaxation times of the DNA internal parameters shift, slide, rise, tilt, roll, and twist. The sequence dependence of fractional occupancies of ions in the major and minor grooves of the DNA is examined, and the possibility of correlation between ion proximity and DNA minor groove widths is investigated. C ounterion structures and motions have been implicated in recent ideas about sequence effects on DNA structure axis curvature and ligand-induced bending (1-7). In each of these theories, the local interactions of ions with polyionic DNA complement the effects described by counterion condensation (CC) theory (8) and the Poisson Boltzmann (PB) equation (9,10). Although the effect of ions and ionic strength on DNA structural and thermodynamics properties are implied from diverse experiments, obtaining a fully detailed molecular model of the ions interacting with DNA based on these results is usually not possible. Oligonucleotide crystal structures reveal only the few ions that are ordered and can be unequivocally assigned. The positions of ions around DNA are generally underdetermined in experiments based on biophysical methods. Recent studies requiring this information have turned to large-scale molecular dynamics (MD) simulations to obtain computational models (11). However, in MD modeling, the complex aggregate of oligonucleotide, water, counterions, and coions is slow to fully stabilize, and ion motions are a rate-determining step in total convergence (12). Current reviews of MD on DNA (12)(13)(14) indicate that all simulations to date are based on considerably shorter trajectories. Therefore, we initiated a project aimed at obtaining demonstrably converged results on ion structures and motions. A related question is the sensitivity of the fast internal motions of the DNA to ion convergence. Our analysis is based on an MD simulation on the prototype B-form duplex d(CGC-GAATTCGCG) in a dilute aqueous solution of water and Na ϩ counterions carried out on a supercomputer until the point of convergence could be reliably determined. The trajectories are used to study the sequence dependence of ion distributions, the DNA-Na ϩ radial distribution functions, and the sensitivity of groove widths to ion proximity. The simulations are used as a basis for a compa...

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“…The assessment of MD simulations was performed using three different metrics-the Pearson's R2, the NOE R-factor and the RMSD calculated as in [11]. The calculations using the three above mentioned approaches were performed for each simulation.…”

Section: Comparison Of Theoretical and Experimental Intensitiesmentioning

confidence: 99%

“…Arthanari et al [11] used the NOESY spectra and scalar couplings to estimate the precision of MD trajectories. However, the level of theory used was insufficient to adequately treat all the effects that influence the experimental spectra.…”

Section: Introductionmentioning

confidence: 99%

Validation of the CHARMM27 force field for nucleic acids using 2D nuclear overhauser effect spectroscopy

Zinovjev¹,

Лиепиньш²

2013

JBPC

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Nuclear magnetic resonance spectroscopy offers a powerful method for validation of molecular dynamics simulations as it provides information on the molecular structure and dynamics in solution. We performed 10 ns MD simulations using the CHARMM27 force field of four palindromic oligonucleotides and compared the results with experimental NOESY data using the full relaxation matrix formalism. The correlation coefficients between theoretical and experimental data for the four molecular species under study ranged from 0.82 to 0.98 confirming the high quality of the selected force field and providing a valid basis for the identification of force field imperfections. Hence, we observed an unsatisfactory treatment of deoxyribose conformational equilibrium, which resulted in the overrepresentation of the energetically favorable C3'-endo conformation in the MD trajectory. Our developed approach for force field validation based on NMR NOESY spectral data is applicable to a wide range of molecular systems and appropriate force fields.

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Assessment of the molecular dynamics structure of DNA in solution based on calculated and observed NMR NOESY volumes and dihedral angles from scalar coupling constants

Cited by 36 publications

References 55 publications

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

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

Ion motions in molecular dynamics simulations on DNA

Validation of the CHARMM27 force field for nucleic acids using 2D nuclear overhauser effect spectroscopy

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