Exploring the quantum mechanical/molecular mechanical replica path method: a pathway optimization of the chorismate to prephenate Claisen rearrangement catalyzed by chorismate mutase

Abstract.

 A replica path method has been developed and extended for use in complex systems involving hybrid quantum/classical (quantum mechanical/molecular mechanical) coupled potentials. This method involves the definition of a reaction path via replication of a set of macromolecular atoms. An “important” subset of these replicated atoms is restrained with a penalty function based on weighted root-mean-square rotation/translation best-fit distances between adjacent (i±1) and next adjacent (i±2) pathway steps. An independent subset of the replicated atoms may be treated quantum mechanically using the computational engine Gamess-UK. This treatment can be performed in a highly parallel manner in which many dozens of processors can be efficiently employed. Computed forces may be projected onto a reference pathway and integrated to yield a potential of mean force (PMF). This PMF, which does not suffer from large errors associated with calculated potential-energy differences, is extremely advantageous. As an example, the QM/MM replica path method is applied to the study of the Claisen rearrangement of chorismate to prephenate which is catalyzed by the Bacillus subtilis isolated, chorismate mutase. Results of the QM/MM pathway minimizations yielded an activation enthalpy ΔH ^†† of 14.9 kcal/mol and a reaction enthalpy of −19.5 kcal/mol at the B3LYP/6-31G(d) level of theory. The resultant pathway was compared and contrasted with one obtained using a forced transition approach based on a reaction coordinate constrained repeated walk procedure (ΔH ^†† =20.1 kcal/mol, ΔH _rxn = −20.1 kcal/mol, RHF/4-31G). The optimized replica path results compare favorably to the experimental activation enthalpy of 12.7±0.4 kcal/mol.