A hypothetical mechanism for HIV-1 integrase catalytic action: DFT modelling of a bio-mimetic environment

Density functional theory computations for a realistic model of the HIV-1 integrase active-site/substrate complex support a single-step reaction for the hydrolysis of phosphodiester bonds, which involves a highly structured SN2-like transition state. Mediation by a stable penta-coordinated intermediate (i.e., the long time postulated dianionic phosphorane) seems lacking. These results call for an energetically favoured divalent cation requiring process coupled to a highly cooperative mechanism, which reduces the activation energy and directs the selectivity for (3′)O–P bond hydrolysis.