Enveloped viruses like HIV, the SARS-CoV facilitate entry into host cells by fusing with the cell membrane, which they achieve by dehydrating it and changing its lipid packing. The high virulence of SARS-CoV-2 (SC-2) is linked to its efficient entry into host cells via membrane fusion, but the precise molecular mechanisms driving its enhanced fusogenic activity remain incompletely understood. This study investigates the interaction of the SARS-CoV-2 fusion peptide (SC-2 FP) with model mammalian membranes, comparing it to its SARS-CoV-1 (SC-1) counterpart to uncover the origins of this enhanced activity, with a particular focus on heterogeneous membrane phases. Employing a multi-modal approach that combines super-resolution STED-fluorescence correlation spectroscopy (STED-FCS), confocal FCS, FRET, and all-atom molecular dynamics (MD) simulations, we comprehensively characterize the FP’s conformational landscape and its impact on membrane dynamics. Our results reveal that the SC-2 FP exhibits a significantly more heterogeneous conformational and binding landscape. This flexibility allows it to partition into distinct subpopulations that are tightly coupled to local lipid environments (Lo vs. Ld phases), resulting in reduced membrane fluidity and increased dehydration—well-known markers of enhanced fusogenic activity. MD simulations corroborate these findings, revealing a rugged binding energy landscape and a wider range of membrane-bound conformations for SC-2 FP, which is driven by the peptide’s unique hydropathic and charge characteristics. By linking the conformational states of the SC-2 FP to its phase-dependent binding and its subsequent modulation of the membrane, our study provides key microscopic signatures that explain its heightened fusogenicity and offers a new paradigm for developing targeted antiviral therapies.
Swarnakar et al. (2026) studied this question.