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All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics.

ABSTRACT: The 27-residue membrane-spanning domain (MSD) of the HIV-1 glycoprotein gp41 bears conserved sequence elements crucial to the biological function of the virus, in particular a conserved GXXXG motif and a midspan arginine. However, structure-based explanations for the roles of these and other MSD features remain unclear. Using molecular dynamics and metadynamics calculations of an all-atom, explicit solvent, and membrane-anchored model, we study the conformational variability of the HIV-1 gp41 MSD. We find that the MSD peptide assumes a stable tilted ?-helical conformation in the membrane. However, when the side chain of the midspan Arg (694) "snorkels" to the outer leaflet of the viral membrane, the MSD assumes a metastable conformation where the highly-conserved N-terminal core (between Lys(681) and Arg(694) and containing the GXXXG motif) unfolds. In contrast, when the Arg(694) side chain snorkels to the inner leaflet, the MSD peptide assumes a metastable conformation consistent with experimental observations where the peptide kinks at Phe(697) to facilitate Arg(694) snorkeling. Both of these models suggest specific ways that gp41 may destabilize viral membrane, priming the virus for fusion with a target cell.

SUBMITTER: Gangupomu VK

PROVIDER: S-EPMC2980712 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics.

Gangupomu Vamshi K VK Abrams Cameron F CF

Biophysical journal 20101101 10

The 27-residue membrane-spanning domain (MSD) of the HIV-1 glycoprotein gp41 bears conserved sequence elements crucial to the biological function of the virus, in particular a conserved GXXXG motif and a midspan arginine. However, structure-based explanations for the roles of these and other MSD features remain unclear. Using molecular dynamics and metadynamics calculations of an all-atom, explicit solvent, and membrane-anchored model, we study the conformational variability of the HIV-1 gp41 MS ...[more]

PMID: 21081093

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Project description:The HIV-1 glycoprotein 41 promotes fusion of the viral membrane with that of the target cell. Structural, biochemical, and biophysical studies suggest that its membrane-proximal external region (MPER) may interact with the HIV-1 membrane and induce its disruption and/or deformation during the process. However, the high cholesterol content of the envelope (ca. 40 to 50 mol%) imparts high rigidity, thereby acting against lipid bilayer restructuring. Here, based on the outcome of vesicle stability assays, all-atom molecular dynamics simulations, and atomic force microscopy observations, we propose that the conserved sequence connecting the MPER with the N-terminal residues of the transmembrane domain (TMD) is involved in HIV-1 fusion. This junction would function by inducing phospholipid protrusion and acyl-chain splay in the cholesterol-enriched rigid envelope. Supporting the functional relevance of such a mechanism, membrane fusion was inhibited by the broadly neutralizing 4E10 antibody but not by a nonneutralizing variant with the CDR-H3 loop deleted. We conclude that the MPER-TMD junction embodies an envelope-disrupting C-terminal fusion peptide that can be targeted by broadly neutralizing antibodies.Fusion of the cholesterol-enriched viral envelope with the cell membrane marks the beginning of the infectious HIV-1 replicative cycle. Consequently, the Env glycoprotein-mediated fusion function constitutes an important clinical target for inhibitors and preventive vaccines. Antibodies 4E10 and 10E8 bind to one Env vulnerability site located at the gp41 membrane-proximal external region (MPER)-transmembrane domain (TMD) junction and block infection. These antibodies display broad viral neutralization, which underscores the conservation and functionality of the MPER-TMD region. In this work, we combined biochemical assays with molecular dynamics simulations and microscopy observations to characterize the unprecedented fusogenic activity of the MPER-TMD junction. The fact that such activity is dependent on cholesterol and inhibited by the broadly neutralizing 4E10 antibody emphasizes its physiological relevance. Discovery of this functional element adds to our understanding of the mechanisms underlying HIV-1 infection and its blocking by antibodies.

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All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics.

Publications

All-atom models of the membrane-spanning domain of HIV-1 gp41 from metadynamics.

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