Accelerated computation of free energy profile at ab initio quantum mechanical/molecular mechanical accuracy via a...

An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical/molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire an AI-QM/MM corrected reaction free energy profile. For three model reactions (identity S_N2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6-31G* level of theory all within 1 kcal mol^-1 with a 20 to 45 fold reduction in the computer time.