QM/MM simulations indicate that Asp185 is the likely catalytic base in the enzymatic reaction of HIV-1 reverse transcriptase

Abstract

Alternative possible mechanisms of reaction in HIV-1 reverse transcriptase are studied here by QM/MM molecular dynamics umbrella sampling simulations. Two protonation states of the dTTP substrate are tested. Among three different pathways, Asp185 is the probable base for deprotonation of the 3′-primer terminus prior to nucleotide addition on fully-deprotonated dTTP with formation of the stable final product complex of DNA_n+1 and PPi. In contrast, the reactions via dTTP or Asp186 as the base show higher energy barriers for either deprotonation or nucleotide addition.