Computational analysis of methyl transfer reactions in dengue virus methyltransferase.

S-Adenosyl-L-methionine (SAM) dependent methyltransferases (MTases) play crucial roles in many biological processes. The MTase of the dengue virus is of particular interest for the development of antiviral drugs against flaviviruses. It catalyzes two distinct methylation reactions at the N7 and the 2'O position of the viral RNA cap structure. Based on density functional theory (DFT) electronic structure calculations, the molecular basis of the underlying chemical reactions involved in the N7 and the 2'O methyl transfer reactions of this enzyme were investigated using model systems. Calculations in the condensed phase show that both reactions are exergonic with significant activation barriers of 13.7 and 17.6 kcal/mol and stable product states, stabilized by 23.5 and 16.9 kcal/mol compared to the reactant states for the N7 and the 2'O reaction, respectively. We find that the reaction rate for the 2'O reaction is significantly enhanced in the presence of the native proton acceptor group, which lowers the activation barrier in the catalyzed reaction by 3.8 kcal/mol compared to the uncatalyzed reaction in aqueous solution. Furthermore, the 2'O reaction involves a methyl and a proton transfer reaction. Our results suggest that these two reactions occur in a concerted fashion in which the methyl group and the proton are transferred simultaneously. From a therapeutic viewpoint, SAM analogues stable under physiological conditions are particularly relevant. One such compound in MeAzaSAM, an isostructural mimic of SAM, for which the present calculations suggest that the methyl transfer reaction is unlikely to occur under biologically relevant conditions.