BPS2026 – SARS-CoV-2 budding is driven by conformation dependent curvature induction of its membrane protein

Assembly and budding of the SARS-CoV-2 virion is driven by interactions between viral structural proteins and the ER-Golgi intermediate compartment (ERGIC) membrane. The viral membrane (M) protein is membrane embedded and exists in either a compact “short” form or an elongated “long” form. Essential for virion formation, M protein guides the assembly of curvature inducing viral protein clusters along the membrane surface, where sufficient curvature induction leads to budding. However, it is unknown whether M protein alone is responsible for inducing this curvature. In this study, all-atom and Martini coarse-grained molecular dynamics simulations show that M protein individually generates membrane curvature with sign dependent on conformation. In its long form, M protein is identified to induce curvature consistent with that of a budding virion, whereas the short form produces curvature resembling the neck during budding. Using coarse-grained simulations of two M proteins, we reveal that membrane curvature governs long-range membrane-mediated M-M interactions, where dissimilar conformations repel each other. To examine higher order oligomerization governed by curvature, we extend this analysis to systems with many M proteins, finding that they contact each other through their C-terminal domains. These simulations elucidate the role of each M protein conformation, showing that their curvature induction facilitates viral budding.