Pi(4,5)P2 Clustering by the Ebola Virus Matrix Protein VP40

Abstract

The Ebola virus protein VP40 is a peripheral protein that is trafficked to the lower leaflet of the plasma membrane. Upon membrane localization in its dimeric form, VP40 undergoes major structural rearrangements to form hexamers which further assemble into filaments and form the viral matrix that provides the major structure for the Ebola virus particles. VP40 hexamers and larger filaments have been shown to be stabilized by PI(4,5)P2 in the plasma membrane inner leaflet. Reduction in the plasma membrane levels of PI(4,5)P2 significantly reduce the formation of VP40 oligomers and virus-like particles. We computationally investigated the lipid-protein interactions in VP40 hexamers at the plasma membrane and quantified lipid-lipid self-clustering by calculating the fractional interaction matrix. We found that the VP40 hexamer significantly enhances the PI(4,5)P2 clustering. The radial pair distribution functions suggest a strong interaction between PI(4,5)P2 and the VP40 hexamer. The cationic side chains are found to mediate the PI(4,5)P2 clustering around the protein, with cholesterol filling the space between the interacting PI(4,5)P2 molecules. These computational studies support recent experimental data and provide new insights into the mechanisms by which VP40 assembles at the plasma membrane inner leaflet, alters membrane curvature, and forms new virus-like particles.