Properties of dianionic oxyphosphorane intermediates from hybrid QM/MM simulation: implications for ribozyme reactions

Abstract

Dianionic oxyphosphorane intermediates have been suggested as good models for studying the mechanisms of self-cleavage reactions undergone by some RNA molecules (the so-called RNA enzymes or ribozymes). We report here the results of a hybrid quantum and molecular mechanical (QM/MM) free energy calculation for obtaining the reaction free energy profiles for such a system. The reactions are simulated in the gas phase as well as within a water sphere in the presence and absence of Mg 2+ ion. The semiempirical quantum mechanical AM1 hamiltonian describes the oxyphosphorane species and the molecular mechanical CHARMM force field describes the solvent and Mg 2+. We find that, when compared with accurate ab initio calculations, the present method shows a tendency to overestimate the stability of the intermediates. On the other hand, it correctly reproduces the qualitative features, namely, the stabilization of the intermediate with solvation and destabilization in the presence of Mg 2+. It also shows a drastic lowering of the barrier for bond cleavage in the presence of Mg 2+, in agreement with ab initio and experimental results. We discuss possible means of increasing the accuracy of the method for subsequent application to modelling the reactions within ribozymes.