I have been involved in the research of DNA structure and its various properties using molecular dynamics simulations and other theoretical techniques.

Molecular Dynamics Studies of Intrinsic and Protein-Induced Effects of DNA Bending in the cAMP receptor protein-DNA Complex.

Abstract: The origin of DNA axis curvature in complexes of the catabolite activator protein with DNA is studied using multiple molecular dynamics (MD) simulations of the free and protein-bound forms of the DNA. The results are compared to available solution and crystal structure data. The MD simulations reproduce the experimentally observed bend in DNA and indicate that ~40% of the bending observed in the complex is intrinsic to the DNA sequence, whereas ~60% is induced on protein binding. The MD provides a model for the dynamical structure of the DNA free in solution and for ligand-induced bending.

Configurational Entropy Change in Protein-DNA Complexes: Estimates from Molecular Dynamics Trajectories.

Abstract: Molecular dynamics (MD) simulations of 5 ns on protein-DNA complexes of catabolite-activator protein (CAP), l-repressor, and their corresponding uncomplexed protein and DNA, are reported. These cases represent two extremes of DNA bending, with CAP DNA bent severely and the l-operator nearly straight when complexed with protein. The calculations were performed using the AMBER suite of programs and the parm94 force field, validated for these studies by good agreement with experimental nuclear magnetic resonance data on DNA. An explicit computational model of structural adaptation and computation of the quasiharmonic entropy of association were obtained from the MD. The results indicate that, with respect to canonical B-form DNA, the extreme bending of the DNA in the complex with CAP is 60% protein-induced and 40% intrinsic to the sequence-dependent structure of the free oligomer. The DNA in the complex is an energetically strained form, and the MD results are consistent with a conformational-capture mechanism. The calculated quasiharmonic entropy change accounts for the entropy difference between the two cases. The calculated entropy was decomposed into contributions from protein adaptation, DNA adaptation, and protein-DNA structural correlations. The origin of the entropy difference between CAP and l-repressor complexation arises more from the additional protein adaptation in the case of l, than to DNA bending and entropy contribution from DNA bending. The entropy arising from protein DNA cross-correlations, a contribution not previously discussed, is surprisingly large.

Curvature in A6-tract DNA Oligonucleotides: Comparison of Molecular Dynamics Model with Results from Crystallography and NMR Spectroscopy.

Simulation Studies On The Role of Ions in Stabilizing Thrombin Binding Aptamer G-Quadruplex .

(In collaboration with Dr. Haribabu Arthanari and Prof Phil Bolton)

Abstract: The DNA aptamer d(GGTTGGTGTGGTTGG) forms an intramolecular G-quadruplex structure in the chair conformation in the presence of K⁺ ions(1). Although the structure of the aptamer has been solved using the NMR technique, technical difficulties make the detection of the ion-binding site location unattainable. Analysis of titration experiments based on NMR indicates that the DNA aptamer – K⁺ quadruplex structure is formed at a stoichiometry of 1:1 although the structure gets fully saturated on formation of 1:2 complex between the aptamer and K⁺. Further, experimental studies also indicate the inability of the aptamer to form the quadruplex structure in the presence of other univalent ions, esp. Na⁺ or in case the guanine at the first position in the aptamer sequence is substituted by 6-thioguanine. These intriguing properties of quadruplex system makes it an ideal candidate for further theoretical simulation studies aimed at developing an insight into the structural and energetic characteristics of the system, inaccessible to direct experimental observation. Here we present a series of long molecular dynamics simulations that explains the experimental observations and helps better understand the physical properties of the quadruplex at the structural level. The simulations have been performed using molecular dynamics procedure based on the Cornell et al. (2) force field using particle mesh Ewald to treat long range electrostatics in this polyionic system. Our results indicate that while the 1:1 complex is formed by intramolecular trapping of the K+ ions between the two G-quartet planes of the quadruplex, the binding of the second K+ ion occurs in a nonspecific fashion, with the ion being externally associated to the loop of the quadruplex. We also present results from a continuum treatment of the electrostatics based on the Poisson-Boltzmann equation to discern the ion binding energetics of the quadruplex system. In particular, the difference in binding free energies for the different cations are studied and compared with results from free energy perturbation studies employing molecular dynamics simulations with explicit solvent.

A novel relational database and web based tools for the analysis of molecular dynamics trajectories of DNA.

Abstract: We report here the release of a web based tool (MDDNA) to study and model the fine structural details of DNA on the basis of data extracted from a set of molecular dynamics (MD) trajectories of DNA sequences involving all the unique tetranucleotides. The dynamic web interface can be employed to analyze the first neighbor sequence context effects on the 10 unique dinucleotide steps of DNA. Functionality is included to build all atom models of any user defined sequence based on the MD results. The backend of this interface is a relational database storing the conformational details of DNA obtained in 39 different molecular dynamics simulation trajectories comprising of all the 136 unique tetranucleotide steps. Examples of the use of this data to predict DNA structures are included.