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

 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. Received: 16 December 2001 / Accepted: 6 September 2002 / Published online: 8 April 2003 Contribution to the Proceedings of the Symposium on Combined QM/MM Methods at the 22nd National Meeting of the American Chemical Society, 2001. Correspondence to: H.L. Woodcock e-mail: hlwood@ccqc.uga.edu Acknowledgements. The authors thank Eric Billings, Xiongwu Wu, and Stephen Bogusz for helpful discussions and related work. The authors also show grateful appreciation to The National Institutes of Health and The National Science Foundation for support of the current research.