ENZYME MECHANISMS WITH HYBRID QUANTUM AND MOLECULAR MECHANICAL POTENTIALS .1. THEORETICAL CONSIDERATIONS

The application of hybrid quantum mechanical and molecular mechanical (QM/MM) potentials to the study of chemical reactions in enzymes is ou tlined. The discussion is general and addresses the difficulties encou ntered in an enzyme QM/MM study. First, general criteria for determini ng whether a particular enzyme is an appropriate candidate for a QM/MM approach are outlined. Methods for obtaining starting structures are detailed. The importance of choosing appropriate levels of ab initio o r semiempirical theory is emphasized. Approaches for interfacing the Q M and MM regions are briefly discussed, with greater detail given to d escribing our CHARMM-GAMESS interface. Techniques for partitioning the system into QM and MM regions are explored. Link atom placement, as d istant from reacting atoms as possible within the confines of computat ional efficiency, is examined in some detail. Methods for determining reaction paths are also discussed. (C) 1996 John Wiley & Sons, Inc.