Modeling Hydrophobic and Hydrophilic Interactions

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DESCRIPTION (provided by applicant): Computer modeling of complex liquids and biological systems is an important tool in biochemistry. With the increasing power of modern computers, it is becoming possible to design new drugs and new biomimetic materials, and to gain understanding of molecular recognition, and the effects of mutations on protein folding. One of the major aims of this proposal is the invention, extension and application of new methods to accelerate the simulation and sampling of conformational states of biomolecular systems. Monte Carlo and molecular dynamics methods for sampling conformational states of biomolecules are often inherently quasi-ergodic. This means that starting in one stable conformation, not all other conformations can be reached on a practical time scale. We aim to devise methods for sampling conformation space in protein systems and other systems characterized by rough energy landscapes, and to apply these new methods to important problems involving the binding of peptides to enzymes and to conformational transitions of peptides.We aim to develop next generation polarizable force fields in order to deal a major impediment to rational drug design. Predictions of binding energies are dependent on the quality of the force field. Existing force fields do not account for known changes in atomic charges when a peptide undergoes a conformation change. Such effects require a chemically accurate polarizable force field that can correctly account for specific hydrogen bonding energies. During the preceding grant period, we based an assigning fluctuating charges and fluctuating dipoles on designated sites on the molecule. This modet has had remarkable success in predicting properties of water, ion solution, amino acids and dipeptides. We have shown that these methods will be used to study conformational dynamics in the (a) of the b-hairpin C-terminus of protein G; (b) the helix-coil transition of homo and hetero oligopeptides; (C) the binding of cyclosporin A to cyclophilin; and (d) conformational transitions in HIV-1 protease.The proposed research will provide new methods and algorithms as well as next generation force field for use in biological simulations. These methods wilt be used to study the binding of cyclosporin A to cvctoohilin and the conformational transitions in HIV-1