Simulations validate a membrane-mechanical hypothesis for the action of an antiviral protein*

IFITM3 is a protein with broad-spectrum anti-viral activity, the exact mechanism of which is not fully known. Experimental studies have pointed to the critical role of its amphipathic helix (AH) domain in inhibiting viral infection. Using molecular dynamics simulations of planar lipid bilayers, in conjunction with a novel theoretical framework for determining mechanical properties of molecular species in multi-component membranes, we determine the intrinsic curvature and thickness preference of IFITM3's AH. We then use continuum modeling to generate simulations of membranes in the hemifusion diaphragm geometry, substantiating the hypothesis that IFITM3 acts by inhibiting the fusion of the viral envelope and late endosomal membranes through stalling this intermediate step in the fusion pathway, driven by the mechanical characteristics of its AH domain.