title: Enhancing Paradynamics for QM/MM Sampling of Enzymatic Reactions.
abstract: Despite the enormous increase in computer power, it is still extremely challenging to obtain computationally converging sampling of ab initio QM/MM (QM(ai)/MM) free energy surfaces in condensed phases. The sampling problem can be significantly reduced by the use of the reference potential paradynamics (PD) approach, but even this approach still requires major computer time in studies of enzymatic reactions. To further reduce the sampling problem we developed here a new PD version where we use an empirical valence bond reference potential that has a minimum rather than a maximum at the transition state region of the target potential (this is accomplished conveniently by shifting the EVB of the product state). Hence, we can map the TS region in a more efficient way. Here, we introduce and validate the inverted EVB PD approach. The validation involves the study of the S(N)2 step of the reaction catalyzed by haloakene dehalogenase (DhlA) and the GTP hydrolysis in the RasGAP system. In addition, we have also studied the corresponding reaction in water for each of the systems described here and the reaction involving trimethylsulfonium and dimethylamine in solution. The results are encouraging and the new strategy appears to provide a powerful way of evaluating QM(ai)/MM activation free energies.
authors: Department of Chemistry (SGM418), University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.|Faculdade de Biotecnologia e Laboratório de Planejamento e Desenvolvimento de Fármacos, Universidade Federal do Pará , 66075-110, Belém, Pará, Brazil.
authors: Jerônimo
authors: J
authors: Lameira
authors: Department of Chemistry (SGM418), University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.
authors: Ilya
authors: I
authors: Kupchencko
authors: Department of Chemistry (SGM418), University of Southern California , 3620 McClintock Avenue, Los Angeles, California 90089, United States.
authors: Arieh
authors: A
authors: Warshel
mesh_terms: D004798:Enzymes / Q000737:chemistry*; D011789:Quantum Theory; D013816:Thermodynamics
chemical_list: D004798:Enzymes