Mechanobiology of viral capsids

The genetic material of a virus is enclosed within a self-assembled protein shell known as a capsid. Because the virus is unable to replicate itself it must deliver its genome at a specific location and time into a target cell. While some capsids must enter intact into the nucleus to avoid detection by the cell, other viruses disassemble in the cytoplasm. Using HIV-1 as a model system, we establish that the cellular site of capsid disassembly is determined by its mechanical properties. Therefore, we study two major events in the replication cycle nuclear entry and capsid uncoating. To address these questions, we will utilize integrative modeling and in-silico atomic force microscopy (AFM). Within our methodology we explicitly examine the capsids

response to simulated expansion of its cargo, for instance, during reverse transcription of the viral genome during uncoating. Our approach involves a stepwise, isotropic expansion, a procedure which mimics increasing internal pressure, and allows us to monitor deformation, rupture, and failure pathways. Through this, we quantify key mechanical metrics like critical volume, Young’s modulus, and rupture dynamics. Our generalizable framework is tested under various conditions, including the presence of IP6, non-infective mutants, and HIV-1 capsids with aberrant morphologies.