A DFT-Based QM-MM Approach Designed for the Treatment of Large Molecular Systems: Application to Chorismate Mutase

A. CRESPO, D. A. SCHERLIS, M. A. MARTI, P. ORDEJON, A. E. ROITBERG, D. A. ESTRIN

JOURNAL OF PHYSICAL CHEMISTRY B

Año: 2003 vol. 107 p. 13728 - 13736

1089-5647

We present a density functional theory (DFT) hybrid quantum mechanical/molecular mechanical (QM-MM)implementation developed for simulations of reactions in complex environments. It is particularly suited tostudy enzyme active sites or solutes in condensed phases. The method combines a QM description of thesolute with a MM treatment of the environment. The QM fragment is treated using DFT as implemented inthe computationally efficient program SIESTA, while the environment is treated using the Wang et al. Amberforce field parametrization. We applied our new QM-MM scheme to study the conversion of chorismate toprephenate by computing the reaction energy profile in vacuo, aqueous solution and in the active site of theB. subtilis chorismate mutase enzyme. We have performed calculations for two different choices of the QMsubsystem in the enzyme simulations: including only the substrate moiety and the substrate plus the chargedside chains glu78 and arg90, respectively. In both cases, our results are in good agreement with experiment.The catalytic activity achieved by chorismate mutase relative to the uncatalyzed reaction in solution is dueto both a minor destabilization of the substrate molecule by compression and a major electrostatic stabilizationof the transition state, which reduce the activation energy of the reaction.