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 cla ssical atomistic molecular dynamics simulations. Previous and novel analysis indicates that the reactive geometry is assisted by a mechanical coupling between the local struct ural fluctuations at the active site and large scale-motion of the entire protein. Additional coarse-grained modeling further allows uncovering unexpected analogies of concert ed large-scale movements across members of the aspartyl-protease family. Taken together, these results may help understand some aspects of the resistance against drugs targeti ng 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 d eterminants 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.