Molecular dynamics simulations of B′-DNA: sequence effects on A-tract-induced bending and flexibility

McConnell, Kevin J.; Beveridge, David L.

doi:10.1006/jmbi.2001.4926

Cited by 64 publications

(66 citation statements)

References 96 publications

(133 reference statements)

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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.

106

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.

106

137

View full text Add to dashboard Cite

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“…From crystal structures and studies in solution, it is generally known for A-tracts in DNA that they develop distinctive B' structure, essentially straight and more rigid than the generic Bform DNA (McConnell and Beveridge, 2001;MacDonald et al, 2000). Such structures induce bending in the molecule, the angle of which depends on the surrounding purine/pyrimidine bases and they can cause increased gel retardation due to enhanced conformation and preferential counterion binding (Stellwagen et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Bogdanova

Markoff²,

Pollmann

et al. 2002

Hum. Mutat.

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Hemophilia A is a common X-linked bleeding disorder caused by various types of mutations in the factor VIII gene F8C. The most common intron 22-inversion is responsible for about 40% of the severe hemophilia A cases while large deletions, point mutations and small (less than 100 bp) deletions or insertions are responsible for the disease in the rest of patients. We report on nine novel (6 deletions, two indels and one partial duplication) and five recurrent small rearrangements identified in 15 German patients with severe hemophilia A, negative for the intron 22-inversion. c.2208-2214delTTATTAC/c.2207-2215insCTCTT and c.4665-4678del/c.4664-4678insAAGGAA identified in the present study are the first small indels described in the factor VIII gene. Our analyses suggest that the prevalence of this type of mutations (predominantly located in exon 14) among patients with severe phenotype and negative for the common intron 22-inversion, is about 30%. The correlation between these molecular defects and formation of factor VIII inhibitors as well as the parental origin of the de novo mutations are evaluated. Finally we show that denaturing HPLC (DHPLC) and classic heteroduplex analysis (HA) are able to detect these sequence alterations on 100% and could be preferred as a screening approach when analysing for mutations in factor VIII in severely affected patients.

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“…In the remaining 1,024 sequences, CArG-boxes or its variants were not found; yet 866 of them contained A-tract sequences (see "Materials and Methods"). This set of binding sites was named "A-tract" and was identified as three or more consecutive A:T bp that are devoid of a TpA step (Strahs and Schlick, 2000;McConnell and Beveridge, 2001;Stefl et al, 2004). We found that 24.8% of the A-tract sites (299 out of 1,204) were in the intergenic and 29.7% (567 out of 1,908) in the gene body data set of OsMADS1-bound sites, respectively.…”

Section: Genome-wide Identification Of Target Genes Bound By Osmads1mentioning

confidence: 94%

Genome-Wide Targets Regulated by the OsMADS1 Transcription Factor Reveals Its DNA Recognition Properties

Khanday

Das²,

Chongloi³

et al. 2016

Plant Physiol.

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ORCID IDs: 0000-0003-4218-0559 (M.B.); 0000-0002-0522-8974 (U.G.).OsMADS1 controls rice (Oryza sativa) floral fate and organ development. Yet, its genome-wide targets and the mechanisms underlying its role as a transcription regulator controlling developmental gene expression are unknown. We identify 3112 geneassociated OsMADS1-bound sites in the floret genome. These occur in the vicinity of transcription start sites, within gene bodies, and in intergenic regions. Majority of the bound DNA contained CArG motif variants or, in several cases, only A-tracts. Sequences flanking the binding peak had a higher AT nucleotide content, implying that broader DNA structural features may define in planta binding. Sequences for binding by other transcription factor families like MYC, AP2/ERF, bZIP, etc. are enriched in OsMADS1-bound DNAs. Target genes implicated in transcription, chromatin remodeling, cellular processes, and hormone metabolism were enriched. Combining expression data from OsMADS1 knockdown florets with these DNA binding data, a snapshot of a gene regulatory network was deduced where targets, such as AP2/ERF and bHLH transcription factors and chromatin remodelers form nodes. We show that the expression status of these nodal factors can be altered by inducing the OsMADS1-GR fusion protein and present a model for a regulatory cascade where the direct targets of OsMADS1, OsbHLH108/ SPT, OsERF034, and OsHSF24, in turn control genes such as OsMADS32 and OsYABBY5. This cascade, with other similar relationships, cumulatively contributes to floral organ development. Overall, OsMADS1 binds to several regulatory genes and, probably in combination with other factors, controls a gene regulatory network that ensures rice floret development.

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Molecular dynamics simulations of B′-DNA: sequence effects on A-tract-induced bending and flexibility

Cited by 64 publications

References 96 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

Prevalence of small rearrangements in the factor VIII gene F8C among patients with severe hemophilia A

Genome-Wide Targets Regulated by the OsMADS1 Transcription Factor Reveals Its DNA Recognition Properties

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