Mechanistic insights into CAM-induced disruption of HBV capsids revealed by all-atom MD simulations

Capsid assembly modulators (CAMs) represent a promising antiviral strategy against hepatitis B virus (HBV), but their effects on preformed capsids remain incompletely understood. Here, all-atom molecular dynamics (MD) simulations of intact HBV capsids complexed with prototypical CAM-As (HAP1, HAP18) and CAM-Es (AT130), reveal how structural changes induced by small molecule binding in the interdimer interfaces propagate through the shell lattice to yield global morphological consequences. Each quasi-equivalent interface exhibits a unique response: A sites, located within the pentameric capsomers, are unfilled in these systems and altered marginally by the presence of CAMs in neighboring interfaces. B sites are the most open and "CAM-ready," suggesting uptake requires minimal conformational perturbation on the local or global level. C sites emerge as hubs of allosteric control and the key drug target, as their occupancy creates local distortion that is broadcast to adjacent sites, driving capsid faceting and - in the case of CAM-As - the destabilization that precedes dissociation in favor of aberrant assembly. D sites, unfilled in these systems, act as structural sinks, absorbing distortions from adjacent interfaces within the hexameric capsomers. The extent of C site adjustment and the nature of D site counterbalance varies with CAM chemotype, highlighting the divergent effects of CAM-As versus CAM-Es. The tensegrity relationship between the four quasi-equivalent interfaces couples them into a global network for strain redistribution that is functionally allosteric, with CAM binding sites displaying signs of both positive and negative cooperativity. These new insights into HBV capsid dynamics clarify how CAMs alter them on the microsecond timescale and suggest that targeting strain redistribution in mature core particles could be leveraged therapeutically. Author summaryHepatitis B is a major cause of chronic liver disease worldwide. The virus relies on a protein shell, called the capsid, to protect and deliver its genetic material to the host cell during infection. Some experimental drug molecules attack this shell, either forcing it to assemble incorrectly or breaking it apart after it has formed. To understand how these molecules work, we used powerful computer simulations to model the capsid at the level of individual atoms. We discovered that when molecules bind the capsid at certain sites, they create strain that spreads across the shell, sometimes leading to large distortions and instability. These insights explain how small molecules can disrupt the virus and point the way toward designing better antiviral therapies.