Simulation Studies on the Role of the M2 Protein in Viral Budding

Abstract

The budding of enveloped viruses is a complex multi-step process requiring alterations in membrane curvature and scission at the neck of the budding virion. M2 is a pH-dependent matrix protein from influenza virus widely known for its role in viral uncoating and the target of the amantadine flu drug that prevents proton transport. An additional role played by M2 relies on collective effects where M2 clusters have been hypothesized to induce local membrane curvature, resulting in a reduced energetic cost associated with the bending of the membrane and where the budding of virus particles takes place in a cholesterol dependent manner (Rossman et al., Cell 142, pp. 902-913, 2010). We use computer simulations to study the effect of M2 tetramers on lipid mixtures consisting of sphingomyelin, DOPC and cholesterol in different ratios and temperatures in a range where lipid mixing and segregation take place. We are working on estimating entropic and free energy contributions to membrane curving and other energetic and structural effects through large-scale simulations with the coarse-grained MARTINI model. These models will form the basis for understanding in detail how M2 induces curvature in membranes as part of the viral budding mechanism in influenza.