First principles molecular dynamics study of catalytic reactions of biological macromolecular systems: toward analyses with QM/MM hybrid molecular simulations.

ABSTRACT

First principles molecular dynamics simulations performed on a fully solvated RNA model structure allowed us to investigate the mechanism for enzymatic cleavage reactions, in vitro, of RNA enzymes (ribozymes). The concerted action of two metal catalysts turns out to be the most efficient way to promote, on the one hand, the proton abstraction from 2(')-OH that triggers the nucleophilic attack and, on the other hand, the cleavage of the P-O(5(')) bond. In fact, the elimination of one of the two metal cations leads to an increase in the activation energy of the reaction. The simulated pathway shows that an OH(-) in the coordination shell of the Mg(2+) close to O(2(')) promotes the initial proton abstraction and prevents its transfer to the ribozyme. This suggests that, in a real ribozyme, the double-metal-ion reaction mechanism is preferred with respect to single-metal-ion mechanisms either in the presence or in absence of the OH(-) anion. Finally, an insight into the importance of hybrid quantum mechanics/molecular mechanics (QM/MM) schemes is discussed in view of the modelling of a realistic system carrying all the features of a true ribozyme.