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.
Keywords: MD simulations ; Bioinformatics ; Qm/Mm ; Coarse-grained ; Dft ; Human-Immunodeficiency-Virus ; Molecular-Dynamics ; Drug-Resistance ; Aspartic Proteases ; Conformational Fluctuations ; Lentivirus Tat ; Ab-Initio ; Inhibitor ; Simulations ; Mechanism
Record created on 2010-11-30, modified on 2016-08-09