Molecular basis for the increased membrane fusion activity of the Ebola virus glycoprotein A82V variant from the 2013-2016 epidemic: insights from simulations and experiments

Abstract

During the 2013-2016 Ebola virus epidemic in Western Africa, an A82V mutation emerged in the envelope glycoprotein (GP) that persisted in most circulating isolates. Previous studies demonstrated that A82V increased GP-mediated membrane fusion and altered its dependence on host factors. The mechanistic basis for these observations, in particular the impact of A82V on the conformational changes in GP that are needed for membrane fusion, has not been evaluated in molecular detail. Here, using a combination of molecular dynamics simulations, fluorescence correlation spectroscopy, and a novel single-molecule Forster resonance energy transfer imaging assay, we specify the molecular mechanism by which A82V alters GP conformation to enhance GP-mediated viral entry. In so doing, we identify an allosteric network of interactions that links the receptor-binding site to the fusion loop of GP. Thus, the naturally occurring A82V mutation can tune the conformational dynamics of EBOV GP to enhance fusion loop mobility and subsequent viral fusion and infectivity in human cells.