Quantum and molecular mechanical Monte Carlo techniques for modeling condensed-phase reactions

A recent review (Acevedo O, Jorgensen WL. Advances in quantum and molecular mechanical (QM/MM) simulations for organic and enzymatic reactions. Acc Chem Res 2010, 43:142-151) examined our use and development of a combined quantum and molecular mechanical (QM/MM) technique for modeling organic and enzymatic reactions. Advances included the pairwise-distance-directed Gaussian (PDDG)/PM3 semiempirical QM (SQM) method, computation of multidimensional potentials of mean force (PMF), incorporation of on-the-fly QM in Monte Carlo simulations, and a polynomial quadrature method for rapidly treating proton-transfer reactions. This article serves as a follow-up on our progress. Highlights include new reactions, alternative SQM methods, a polarizable OPLS force field, and novel solvent environments, e.g., 'on water' and room temperature ionic liquids. The methodology is strikingly accurate across a wide range of condensed-phase and antibody-catalyzed reactions including substitution, decarboxylation, elimination, isomerization, and pericyclic classes. Comparisons are made to systems treated with continuum-based solvents and ab initio or density functional theory (DFT) methods. Overall, the QM/MM methodology provides detailed characterization of reaction paths, proper configurational sampling, several advantages over implicit solvent models, and a reasonable computational cost.