Path Integral-Free Energy Perturbation (PI-FEP) Simulations: Kinetic Isotope Effects of Proton/Deuteron Transfer Reactions in Aqueous Solution

We present a tutorial review of the theoretical background and a step-by-step computational procedure for determining kinetic isotope effects (KIEs) of chemical reactions in aqueous solution. The method combines path integral and free energy perturbation (PI-FEP) simulations to directly yield the ratio of the partition functions between different isotopic reactions. This review is the result of collaborative work in a Computational Chemistry course at the University of Minnesota, where two intramolecular proton-transfer reactions were given as classroom exercises. Through this study, we wish to accomplish three main goals: (i) determination of nuclear quantum effects and quantum-mechanical potentials of mean force (QM-PMF), (ii) computation of primary KIE using PI-FEP simulations, and (iii) an understanding of solvent effects on proton-transfer reactions in water. Analyses of computational results provide insights into substituent effects on chemical reactivity, solvent effects on reaction rate, nuclear quantum effects on free energy barrier, and KIEs on transition state. The theory and computational procedure for determining KIE can be directly used to study chemical reactions in solutions and enzymatic processes with two publicly available software packages (CHARMM and QBICS). This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Structure and Mechanism > Reaction Mechanisms and Catalysis.