SARS-CoV-2 membrane protein conformations induce distinct membrane curvatures
The assembly and budding of enveloped viruses requires thousands of membrane proteins to collectively remodel host-cell membranes into highly curved virions. In SARS-CoV-2, this process is driven by interactions between viral structural proteins and the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane. The membrane (M) protein, an embedded homodimer and the most abundant viral component, exists in two conformations: a compact "short" form and an elongated "long" form. Although M is essential for virion assembly, how its conformations contribute to the generation and organization of the membrane curvature required for budding has remained unknown. Here, we used all-atom and Martini coarse-grained molecular dynamics simulations to show that individual M proteins can induce distinct membrane curvatures, depending on their conformation. The long form bends the membrane around its C-terminal, forming a valley-like depression, while the short form predominantly bends the membrane away from the C-terminal producing an anisotropic ridge. The induced curvatures correspond to the bulb and neck regions of a budding virion, respectively. Coarse-grained simulations of M protein pairs further reveal that curvature modulates long-range, membrane-mediated M-M interactions, leading to repulsion between dissimilar conformations. Together, these results suggest that the long and short forms of M naturally segregate to shape the virions bulb and neck, potentially facilitating genome encapsulation and membrane scission. This mechanism provides a physical basis for coronavirus budding and suggests that conformationally encoded curvature fields may represent a general principle underlying the formation of enveloped viruses. Significance StatementEnveloped viruses must bend host cell membranes to form new viral particles, but the driving force for membrane bending has been unclear. Using molecular dynamics simulations, we show that the SARS-CoV-2 membrane protein, the most abundant structural protein of the virus, drives membrane bending, and that its two natural conformations generate opposite signs of curvature which match the geometry of distinct regions of a budding virus. Moreover, these induced curvatures cause proteins in different conformations to repel one another providing a physical basis for their spatial segregation. Our results suggest that the membrane proteins conformations can contribute significantly to the membrane remodeling needed for virus assembly and release, revealing a simple mechanism that may apply to other enveloped viruses.