First-principles determination of free energy profiles (FEP) for condensed-phase chemical reactions in quantum mechanical/molecular mechanical (QM/MM) simulations is computationally demanding because of the daunting costs associated with conducting statistical sampling on hybrid potentials that combine ab initio (AI) electronic structure methods with molecular mechanics (AI/MM). To address this challenge, we have developed the Reaction Path-Force Matching method in Collective Variables (RP-FM-CV) which enables efficient AI/MM-FEP simulations through mean force fitting. In this method, minimum free energy pathway (MFEP) in CVs is first determined in condensed phase on an efficient reactive aiding potential. Based on configurations sampled along MFEP, forces on CVs are then modified to reproduce the corresponding free energy mean forces determined at the target AI/MM levels through force matching. In this work, we demonstrate the effectiveness of the RP-FM-CV method on two solution-phase SN2 reactions, namely, the Cl- + CH3Cl (Finkelstein) and NH3 + CH3Cl (Menshutkin) reactions, in explicit-water QM/MM simulations. Employing the semiempirical AM1/MM Hamiltonian as the aiding potential, we have determined AI/MM-FEPs for these reactions at density functional theory (DFT) and second-order Møller-Plesset perturbation (MP2) levels. Comparisons with the experimental and benchmark results suggest that RP-FM-CV can be used as an efficient and reliable method for simulating solution-phase chemical reactions.

Reaction path-force matching in collective variables: Determining ab initio QM/MM free energy profiles for solution-phase reactions

255th National Meeting (2018)

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