We request herein continuation support for the study of the structure and dynamics of biological macromolecules using Molecular Dynamics (MD) and Monte Carlo (MC) computer simulation methods. The focus of our research involves development and robust simulation protocols for application to the above systems, detailed characterization of the ensuing trajectories and establishment of the feasibility, accuracy and limitations of the MC methodology as applied to these systems. The studies proposed herein will focus in four areas: a) critical assessment of the applicability of current MC simulation protocols to longer DNA oligonucleotides, varying in length from about 17-30 base pairs; b) dynamical structure of DNA sequences important in the regulation of physiological processes through bending and/or protein recognition and c) structural studies and mechanistic implications derived from solution simulations of an enzyme complexed with an inhibitor/substrate and d) MD/MC simulations of proteins involved in DNA sequence recognition that are significant towards understanding the molecular basis of gene expression. The emphasis in our projects is on detailed structural characterization based on a variety of force fields, scrutinization of the results with crystallographic, NMR and other available experimental data, identifying and analyzing substates and development of state of the art graphical analysis tools.
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