We request herein continuation support for theoretical and computational studies on systems of biological molecules using molecular simulation procedures, i.e., Monte Carlo (MC) and molecular dynamics (MD) calculations. Studies in previous project periods have dealt with fundamental issues in water and aqueous solution structure relevant to biomolecular systems, and the hydration of protein and nucleic acid constituents. Emphasis in the proposed project period will be placed on the structure and dynamics of oligonucleotide duplexes and related molecular complexes in crystal hydrates and in solution. In these systems, solvent effects (hydration and ion atmosphere) are well known to be of crucial significance, but their operative nature is not yet well understood nor fully accounted for by theoretical calculations. With the present generation of supercomputers, attached processors and graphic workstations, the capability of molecular simulation to treat rigorously and extensively systems of the dimensionality required for including solvent effects with biological molecules has now been minimally achieved, and computer capabilities are developing rapidly. The principal theoretical and computational methodologies for molecular simulation are available in or accessible via NSFnet from this laboratory. The proposed studies build upon recent force field developments, advances in methodology and particularly new and novel procedures for analysis of MD results on DNA using molecular graphics to carry forward timely theoretical investigations and specific applications of molecular simulation in the area of nucleic acids research. Proposed projects include the further determination and analysis of hydration density distributions in oligonucleotides and canonical forms of DNA, free energy simulation studies of the A to B transition, MC studies of counterion distributions as a function of salt and dielectric effects, a new graphical analysis of MD calculations on DNA in terms of a complete set of conformational, helicoidal and junction parameters, a morphological classification of oligonucleotide crystal structure data on this basis, MD studies of the dCpG/proflavin crystal hydrate, characterization studies of nucleic acid force fields and electrostatic modelling, protocols for use of restrained MD and MC Boltzmann jump methods with 20- NOESY distance information for determination of solution structure of intact and damaged sequences implicated in DNA repair, and a study of the effects of hydration, salt and flanking sequence on a 12-mer containing the GAATTC protein binding site
| Lavery, Richard; Zakrzewska, Krystyna; Beveridge, David et al. (2010) A systematic molecular dynamics study of nearest-neighbor effects on base pair and base pair step conformations and fluctuations in B-DNA. Nucleic Acids Res 38:299-313 |
| Sen, Sobhan; Andreatta, Daniele; Ponomarev, Sergei Y et al. (2009) Dynamics of water and ions near DNA: comparison of simulation to time-resolved stokes-shift experiments. J Am Chem Soc 131:1724-35 |
