HYBRID CLASSICAL-QUANTUM FORCE-FIELD FOR MODELING VERY LARGE MOLECULES

A coherent computational scheme on a very large molecule in which the subsystem that undergoes the most important electronic changes is trea ted by a semiempirical quantum chemical method, though the rest of the molecule is described by a classical force field, has been proposed r ecently. The continuity between the two subsystems is obtained by a st rictly localized bond orbital, which is assumed to have transferable p roperties determined on model molecules. The computation of the forces acting on the atoms is now operating, giving rise to a hybrid classic al quantum force field (CQFF) which allows full energy minimization an d modeling chemical changes in large biomolecules. As an illustrative example, we study the short hydrogen bonds and the proton-exchange pro cess in the histidine-aspartic acid system of the catalytic triad of h uman neutrophil elastase. The CQFF approach reproduces the crystallogr aphic data quite well, in opposition to a classical force field. The m ethod also offers the possibility of switching off the electrostatic i nteraction between the quantum and the classical subsystems, allowing us to analyze the various components of the perturbation exerted by th e macromolecule in the reactive part. Molecular dynamics confirm a fas t proton exchange between the three possible energy wells. The method appears to be quite powerful and applicable to other cases of chemical interest such as surface reactivity of nonmetallic solids. (C) 1996 J ohn Wiley & Sons, Inc.