The generalized hybrid orbital method for combined quantum mechanical/molecular mechanical calculations: formulation and tests of the analytical derivatives

Hybrid quantum mechanical (QM) and molecular mechanical (MM) potentials are becoming increasingly important for studying condensed-phase systems but o ne of the outstanding problems in the field has been how to treat covalent bonds between atoms of the QM and MM regions. Recently, we presented a gene ralized hybrid orbital (GHO) method that was designed to tackle this proble m for hybrid potentials using semiempirical QM methods [Gao et al. (1998) J Phys Chem A 102: 4714-4721]. We tested the method on some small molecules and showed that it performed well when compared to the purely QM or MM pote ntials. In this article, we describe the formalism for the determination of the GHO energy derivatives and then present the results of more tests aime d at validating the model. These tests, involving the calculation of the pr oton affinities of some model compounds and a molecular dynamics simulation of a protein, indicate that the GHO method will prove useful for the appli cation of hybrid potentials to solution-phase macromolecular systems.