Study of the conformational dynamics of the catalytic loop of WT and G140A/G149A HIV-1 integrase core domain using reversible digitally filtered molecular dynamics

The HIV-1 IN enzyme is one of three crucial virally encoded enzymes (HIV-1 IN, HIV-1 PR, and HIV-1 RT) involved in the life-cycle of the HIV-1 virus, making it an attractive target in the development of drugs against the AIDS virus. The structure and mechanism of the HIV-1 IN enzyme is the least understood of the three enzymes due to the lack of three-dimensional structural information. X-ray cystallographic studies have not yet been able to resolve the full-length structure, and studies have been mainly focused on the catalytic domain. This central domain possesses an important catalytic loop observed to overhang the active site, and experimental studies have shown that its dynamics affects the catalytic activity of mutant HIV-1 IN enzymes. In this study, the enhanced sampling technique, Reversible Digitally Filtered Molecular Dynamics (RDFMD), has been applied to the catalytic domain of the WT and G140A/G149A HIV-1 IN enzymes and has highlighted significant differences between the behavior of the catalytic loop which may explain the decrease of activity observed in experimental studies for this mutant