A Quantum Chemical Approach to Reactions in Biomolecules

Abstract

In order to overcome the limitations of conventional molecular mechanics and quantum mechanics studies of model systems, we recently proposed a coherent computational scheme, for very large molecules, in which the subsystem that undergoes the most important electronic changes is treated by a semi-empirical quantum chemical method, though the rest of the molecule is described by a classical force field. The continuity between the two subsystems is obtained by a strictly localized bond orbital, which is assumed to have transferable properties determined on model molecules. The computation of the forces acting on the atoms is now operative, giving rise to a hybrid Classical Quantum Force Field (CQFF) which allows full energy minimization and the modelling of chemical changes in large biomolecules.

As illustrative examples we present the proton exchange process in the histidine–aspartic acid system of the catalytic triad of human neutrophil elastase and the inhibition of the charge relay system in the trypsin-BPTI complex. In contrast to a classical force field, the CQFF approach reproduces the crystallographic data quite well. The method also offers the possibility of switching off the electrostatic interaction between the quantum and the classical subsystems allowing us to analyze the various components of the perturbation exerted by the macromolecule in the reactive part. Molecular dynamics confirms a fast proton exchange between the three possible energy wells in HNE. We also explain the inhibition of trypsin by BPTI by a perturbation of the catalytic triad geometry of trypsin in the presence of BPTI.