The research program centers on the development and application of quantitative methods for exploring the structure, energetics and reactivity of biomolecular systems. Such work is needed for the deeper understanding of biochemical structure and function and for the improvement of predictive skills of importance in many areas including the rational design of therapeutic drugs. The present theoretical approach centers on computer simulations of the biomolecular systems at the atomic level with explicit inclusion of the solvent. The principal techniques that are used are Monte Carlo statistical mechanics and molecular dynamics with emphasis on computing changes in free energy for transformations in solution. The specific focus of the proposal is the energetics and dynamics of peptides and proteins. Efforts will be directed at (1) expansion of the capabilities of the BOSS Monte Carlo program for facile treatment of polypeptides and compounds with flexible rings, (2) quantitative investigations of factors that influence the stability of proteins and structured peptides including the effects of charge - helix dipole interactions and salt bridge formation, (3) quantitative investigation of the intrinsic helix forming propensity of individual residues including the development of a theoretical helicity scale, (4) quantitative investigation of the competition between formation of alpha and 310 helices as a function of sequence and helix length, (5) molecular dynamics studies of the unfolding of helical peptides and disulfideless proteins as a route to insights on protein unfolding and folding, and (6) studies of the immunosuppressive agents, FK506 and rapamycin, and the FK506 binding protein, FKBP, including conformational analyses and assessment of the effects of structural modifications on complexation.
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