QUANTUM-MECHANICAL COMPUTATIONS ON VERY LARGE MOLECULAR-SYSTEMS - THELOCAL SELF-CONSISTENT-FIELD METHOD

Quantum chemical computations on a subset of a large molecule can be p erformed, at the neglect of diatomic differential overlap (NDDO) level , without further approximation provided that the atomic orbitals of t he frontier atoms are replaced by parametrized orthogonal hybrid orbit als. The electrostatic interaction with the rest of the molecule, trea ted classically by the usual molecular mechanical approximations, is i ncluded into the self-consistent field (SCF) equations. The first and second derivatives of energy are obtained analytically, allowing the s earch for energy minima and transition states as well as the resolutio n of Newton equations in molecular dynamics simulations. The local sel f-consistent field (LSCF) method based on these approximations is test ed by studying the intramolecular proton transfer in a Gly-Arg-Glu-Gly model tetrapeptide, which reveals an excellent agreement between a co mputation performed on the whole molecule and the results obtained by the present method, especially if the quantum subsystem includes the s ide chains and the peptidic unit in between. The merits of the LSCF me thod are examplified by a study of proton transfer in the Asp(69)-Arg( 71) salt bridge in dihydrofolate reductase. Simulations of large syste ms, involving local changes of electronic structure, are therefore pos sible at a good degree of approximation by introducing a quantum chemi cal part in molecular dynamics studies. This methodology is expected t o be very useful for reactivity studies in biomolecules or at the surf ace of covalent solids. (C) 1994 by John Wiley and Sons, Inc.