Modeling of biomolecular systems with the quantum mechanical and molecular mechanical method based on the effective fragment potential technique: Proposal of flexible fragments

Development and applications of a new approach to hybrid quantum mechanical and molecular mechanical (QM/MM) theory based on the effective fragment potential (EFP) technique for modeling properties and reactivity of large molecular systems of biochemical significance are described. It is shown that a restriction of frozen internal coordinates of effective fragments in the original formulation of the theory (Gordon, M.. S.; Freitag, M. A.; Bandyopadhyay, P.; Jensen, J. H.; Kairys, V.; Stevens, W. J. J. Phys. Chem. A 2001, 105, 293) can be removed by introducing a set of small EFs and replacing the EFP-EFP interactions by the customary MM force fields. The concept of effective fragments is also utilized to solve the QM/MM boundary problem across covalent bonds. The buffer fragment, which is common for both subsystems, is introduced and treated specially when energy and. energy gradients are computed. An analysis of conformations of dipeptide-water complexes, as well as of dipepties with His and Lys residues, confirms the reliability of the theory. By using the Hartree-Fock and MP2 quantum chemistry methods with the OPLS-AA molecular mechanical force fields, we calculated the energy difference between the enzyme-substrate complex and the first tetrahedral intermediate for the model active site of the serine protease catalytic system. In another example, the multiconfigurational complete active space self-consistent field (CASSCF) method was used to model the homolytic dissociation of the peptide helix over the central C-N bonds. Finally, the potentials of internal rotation of the water dimer considered as a part of the water wire inside a polyglycine analogue of the ion channel gramicidin A were computed. In all cases, an importance of the peptide environment from MM subsystems on the computed properties of the quantum parts is demonstrated.