Multi-scale modeling of HIV-1 proteins

The efficiency of protease inhibiting drugs is hampered by the rapid emergence of protease variants. Understanding this phenomenon requires the characterization of the salient steps of HIV-1 protease's catalytic cycle. We summarize our investigations on the reactive geometry of the protease-substrate complex based on first principles, QM/MM and classical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local structural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concerted large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeting HIV-1 protease. We further present computational studies on HIV-1 transactivator of transcription (Tot) viral RNA binding protein. Interfering with Tat/TAR interactions is a promising strategy for anti-AIDS intervention. We have identified conserved structural and energetic features among different protein isolates and predicted the structural determinants of Tat in complex with one of the host cell cognate proteins, p/CAF. These findings may help the design of ligands interfering with Tat function.