Surjit B. Dixit

A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA

It is well recognized that base sequence exerts a significant influence on the properties of DNA and plays a significant role in protein–DNA interactions vital for cellular processes. Understanding and predicting base sequence effects requires an extensive structural and dynamic dataset which is currently unavailable from experiment. A consortium of laboratories was consequently formed to obtain this information using molecular simulations. This article describes results providing information not only on all 10 unique base pair steps, but also on all possible nearest-neighbor effects on these steps. These results are derived from simulations of 50–100 ns on 39 different DNA oligomers in explicit solvent and using a physiological salt concentration. We demonstrate that the simulations are converged in terms of helical and backbone parameters. The results show that nearest-neighbor effects on base pair steps are very significant, implying that dinucleotide models are insufficient for predicting sequence-dependent behavior. Flanking base sequences can notably lead to base pair step parameters in dynamic equilibrium between two conformational sub-states. Although this study only provides limited data on next-nearest-neighbor effects, we suggest that such effects should be analyzed before attempting to predict the sequence-dependent behavior of DNA.

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

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.

Spectroscopic and Molecular Dynamics Evidence for a Sequential Mechanism for the A-to-B Transition in DNA ☆

The A-to-B form transition has been examined in three DNA duplexes, d(CGCGAATTCGCG)(2), d(CGCGAATTGCGC), and d(CGCAAATTTCGC), using circular dichroism spectroscopy, ultraviolet resonance Raman (UVRR) spectroscopy, and molecular dynamics (MD) simulation. Circular dichroism spectra confirm that these molecules adopt the A form under conditions of reduced water activity. UVRR results, obtained under similar conditions, suggest that the transition involves a series of intermediate forms between A and B. Cooperative and distinct transitions were observed for the bases and the sugars. Independent MD simulations on d(CGCGAATTCGCG)(2) show a spontaneous change from the A to B form in aqueous solution and describe a kinetic model that agrees well with UVRR results. Based on these observations, we predict that the mechanism of the transition involves a series of A/B hybrid forms and is sequential in nature, similar to previous crystallographic studies of derivatized duplexes. A simulation in which waters were restrained in the major groove of B DNA shows a rapid, spontaneous change from B to A at reduced water activity. These results indicate that a quasiergodic sampling of the solvent distribution may be a problem in going from B to A at reduced water activity in the course of an MD simulation.

Prokaryotic Gene Finding Based on Physicochemical Characteristics of Codons Calculated from Molecular Dynamics Simulations

An ab initio model for gene prediction in prokaryotic genomes is proposed based on physicochemical characteristics of codons calculated from molecular dynamics (MD) simulations. The model requires a specification of three calculated quantities for each codon: the double-helical trinucleotide base pairing energy, the base pair stacking energy, and an index of the propensity of a codon for protein-nucleic acid interactions. The base pairing and stacking energies for each codon are obtained from recently reported MD simulations on all unique tetranucleotide steps, and the third parameter is assigned based on the conjugate rule previously proposed to account for the wobble hypothesis with respect to degeneracies in the genetic code. The third interaction propensity parameter values correlate well with ab initio MD calculated solvation energies and flexibility of codon sequences as well as codon usage in genes and amino acid composition frequencies in approximately 175,000 protein sequences in the Swissprot database. Assignment of these three parameters for each codon enables the calculation of the magnitude and orientation of a cumulative three-dimensional vector for a DNA sequence of any length in each of the six genomic reading frames. Analysis of 372 genomes comprising approximately 350,000 genes shows that the orientations of the gene and nongene vectors are well differentiated and make a clear distinction feasible between genic and nongenic sequences at a level equivalent to or better than currently available knowledge-based models trained on the basis of empirical data, presenting a strong support for the possibility of a unique and useful physicochemical characterization of DNA sequences from codons to genomes.