(626g) Conformational Prediction of the Membrane-Spanning Domain of HIV-1 gp41

The HIV-1 envelope glycoprotein (Env) is a trimer of heterodimers of receptor-targeting gp120 and membrane-anchoring gp41 fragments that mediates infection by recognizing and binding cell-surface CD4 and CCR5/CXCR4 receptors and undergoing a series of poorly characterized conformational changes that drive fusion of viral and cell compartments. We use a combination of all-atom molecular dynamics and metadynamics to probe the free energy of the membrane-spanning domain (MSD) of gp41 in both water and in a viral lipid bilayer to provide a basis for hypothesizing how the Env-mediated fusion reaction occurs in molecular detail. In water, we find that MSD shuttles between two kinked partially helical conformational states. Metadynamics calculations of MSD's spanning cholesterol-containing lipid bilayers indicate that a canonical membrane-spanning α-helix is less stable than a kinked conformaiton in which the midspan arginine, R694, ?snorkels? its side-chain among the head groups of either leaflet, supporting interpretations of recent mutagenesis work. Importantly, this snorkling conformation is observed to thin the membrane, which could conceivable reflect that part of the fusion mechanism involves viral protein-membrane configurations in which the membrane is relatively unstable.