The objectives of this research program are to investigate dynamical structures, molecular motions, solvation and ligand interactions of DNA oligonucleotides in solution and crystalline solids using molecular dynamics (MD) computer simulation and other theoretical and computational methodologies available to molecular biophysics. All MD simulations will include water and counterions explicitly for run lengths extending at least into the nanosecond regime of time. Continuation studies are proposed on shorter oligonucleotide sequences for further characterization and assessment of MD modeling capabilities and limitations via comparison with observed structures obtained from crystallography and NMR, and state of the art quantum mechanical calculations on fragments. Further development and implementation of analysis techniques for elucidation of the structural chemistry and dynamics of solvent water and mobile ions will be carried out, including elaboration of a new method aimed at providing the missing link between solvent structure and functional energetics. Applications of MD modeling to the elucidation of basepair sequence effects on structure and axis bending will be pursued on both shorter (10-12 bp) and longer ( up to 40 bp) oligonucleotides. The fundamental nature of sequence effects, still unsettled at the theoretical level, will be explored via analysis of accurate MD results in the context of current hypotheses about the competing effects of van der Waals clashes, dispersion forces, electrostatic interactions, and solvent effects at the basepair level. An alternative perspective on this subject will be created based on MD studies of the effect structural perturbations such as modified backbones and bases. New research initiatives are directed at the critical use of MD in ligand binding studies, and developing links between all atom MD modeling and terms in free energy component analysis of ligand binding processes that are otherwise difficult to estimate accurately. A critical examination of the component analysis approach will be carried out with respect to estimated errors and uncertainties in the various terms and the calculated net binding energies. Analysis methodologies for the structure, motions, solvation of nucleic acid systems will be implemented in version 3.0 of """"""""Molecular Dynamics Tool Chest"""""""" and made available for general distribution. Building on our participation in the Nucleic Acids Data Base Project, the articulation of MD results on DNA systems with the field of nucleic acid structural bioinformatics will developed into a state of broader general utility to the field. Successful completion of the proposed research will advance our understanding of the dynamical structure of nucleic acids in solution, effects of sequence on DNA structure and axis bending important in molecular recognition processes, forge improved links between dynamical structure and functional energetics, and contribute to an improved understanding of the thermodynamics of nucleic acid-ligand binding processes.
| Singhal, Poonam; Jayaram, B; Dixit, Surjit B et al. (2008) Prokaryotic gene finding based on physicochemical characteristics of codons calculated from molecular dynamics simulations. Biophys J 94:4173-83 |
