A research project aimed at developing the capacity for theoretical characterization of biomolecular interactions and enzymatic processes in solution is proposed. The theoretical approach centers on computer simulations of proteins at the atomic level using molecular dynamics techniques. To provide an accurate description of intermolecular interactions for chemical and photochemical processes in biological systems, a combined quantum mechanical and molecular mechanical (QM/MM) approach is being developed. A key feature of the proposed method is the incorporation of a polarizable intermolecular potential function (PIPF) into the combined QM/MM method for both the ground and excited state calculations. Thus, condensed phase polarization effects on both the quantum-mechanically treated substrate molecule and the rest of the protein/solvent system will be consistently determined in the combined QM/PIPF approach. In addition, a localized bond orbital method will be used to improve and properly address the division of covalent bonds across the QM and MM regions for application in enzymatic processes. A major thrust will be investigations of the structure and dynamics of bacteriorhodopsin. A novel approach to the active site structural refinement of the membrane protein baceriorhodopsin is being developed. The procedure involves reproduction of the experimental absorption spectra and opsin shifts through molecular dynamics calculations using the combined Q< configuration interaction and PIPF method. The structural modeling will be followed by simulation of the primary photoisomerization reaction and proton translocation in bacteriorhodopsin through a series of excited-state trajectory and free- energy calculations. In addition, the Claisen rearrangement of chorismate to prephenate in chorismate mutase and in a catalytic antibody will be modeled to gain structural and electrostatic insight into enzyme catalysis. Initial studies will include determination of the potential of mean force for the reaction in aqueous solution and in the native protein. Subsequent work on the process in the catalytic antibody will lead to predictions of amino acid substitutions that may improve the catalytic efficiency of the catalytic antibody.
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