Biophysical Society Thematic Meeting | Ascona 2026

Mechanobiology of Infection

Wednesday Speaker Abstracts

MECHANISM OF VIRAL PROTEIN-MEDIATED MEMBRANE FUSION Sandrasegaram Gnanakaran Los Alamos National Laboratory, Los Alamos, NM, USA The HIV-1 envelope (Env) glycoprotein is a trimeric gp120/gp41 complex expressed on the viral surface that mediates entry into host cells, analogous to the fusion proteins of other enveloped viruses such as influenza, and coronaviruses. Unlike other viruses, however, HIV-1 can accomplish membrane fusion with only a small number of Env trimers, on the order of a dozen. The early steps of HIV-1 entry are well characterized: gp120 binds the CD4 receptor on human T cells and subsequently engages the coreceptors CCR5 or CXCR4. In contrast, the molecular details of the later stages of entry, including the conformational transitions of gp41 from the pre hairpin intermediate to the post-fusion state, remain poorly understood. In particular, the protein driven membrane remodeling events that lead to fusion pore formation have resisted detailed mechanistic analysis. To address this gap, we used structure-based simulations at two levels of resolution, all-atom and coarse-grained, to track both protein conformational dynamics and lipid rearrangements during fusion of the viral and host membranes. These models were complemented by extensive biased and unbiased all-atom and coarse-grained molecular dynamics simulations to characterize intermediate states along the fusion pathway. Together, these approaches capture conformational dynamics spanning the pre-fusion to post-fusion transition. Importantly, simulations of gp41 embedded in lipid bilayers designed to mimic the asymmetric composition of viral and host membranes revealed membrane perturbations, including changes in leaflet density, bilayer thickness, and disruptions in local lipid compisition. These features are consistent with cryo-electron tomography observations. We further show that local cholesterol enrichment plays a critical role in the membrane fusion events observed by cryo-ET and reproduced in simulations. Using an integrated cryo-ET and computational framework, we visualize the pathway of HIV-1 Env-mediated membrane fusion and define molecular details of the mechanobiology underlying protein-mediated membrane docking, lipid mixing, membrane merger, and fusion pore opening.

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