Molecular basis for the increased fusion activity of the Ebola virus glycoprotein epidemic variant A82V: Insights from simulations and experiments

Natasha D Durham; Aastha Jain; Angela Howard; Jeremy Luban; James B Munro

doi:10.1016/j.celrep.2025.115521

Molecular basis for the increased fusion activity of the Ebola virus glycoprotein epidemic variant A82V: Insights from simulations and experiments

Cell Rep. 2025 Apr 3;44(4):115521. doi: 10.1016/j.celrep.2025.115521. Online ahead of print.

Authors

Natasha D Durham¹, Aastha Jain², Angela Howard³, Jeremy Luban⁴, James B Munro⁵

Affiliations

¹ Department of Microbiology, UMass Chan Medical School, Worcester, MA 01605, USA. Electronic address: natasha.durham@umassmed.edu.
² Department of Microbiology, UMass Chan Medical School, Worcester, MA 01605, USA.
³ Program in Molecular Microbiology, Tufts University Graduate School of Biomedical Sciences, Boston, MA 02111, USA.
⁴ Program in Molecular Medicine, UMass Chan Medical School, Worcester, MA 01605, USA.
⁵ Department of Microbiology, UMass Chan Medical School, Worcester, MA 01605, USA; Department of Biochemistry and Molecular Biotechnology, UMass Chan Medical School, Worcester, MA 01605, USA. Electronic address: james.munro@umassmed.edu.

PMID: 40186866
DOI: 10.1016/j.celrep.2025.115521

Abstract

During the 2013-2016 Ebola virus (EBOV) 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 molecular dynamics simulations, fluorescence correlation spectroscopy, and single-molecule Förster resonance energy transfer imaging, we specify the molecular mechanism by which A82V alters GP conformation to enhance 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.

Keywords: CP: Microbiology; CP: Molecular biology; Ebola virus; conformational dynamics; envelope glycoprotein; fluorescence correlation spectroscopy; molecular dynamics simulation; single-molecule FRET imaging; virus entry.