Abstract
The accurate calculation of free-energy profiles for condensed-phase and enzymatic reactions is often computationally demanding when employing traditional methods such as a combined quantum and molecular mechanical (QM/MM) simulation featuring configurational sampling. A novel polynomial fitting and analytical integration method was recently developed for proton transfer reactions that provides a seven-fold enhancement to the calculation speed compared with traditional potentials of mean force (PMF) methods and yields close agreement with experimental free energies of activation. In addition, the expansion of PMF simulations to monitor three simultaneous reaction coordinates was also reported to enhance phase space sampling, which is useful for accurately elucidating complex reaction mechanisms. This review focuses upon the development of these methods and their utility is illustrated in recent examples including hydrolysis reactions in fatty acid amide hydrolase, Kemp elimination reactions in antibody 4B2 and ionic liquid environments, and condensed-phase singlet oxygen ene reactions.
