THE HEPATITIS B CAPSID: CHARACTERIZING A VIRAL SHAPESHIFTER THROUGH THE COMPUTATIONAL MICROSCOPE

The hepatitis B virus (HBV) capsid is a remarkable molecular machine that performs multiple, distinct functions throughout the viral life cycle, despite being composed of a relatively small protein. This functional versatility arises from its ability to access a diverse ensemble of conformational states that regulate assembly, host interactions, and response to antiviral molecules. However, many of these states remain inaccessible to experimental structural techniques, which often provide averaged or static views of the particle. In this work, we employ all-atom molecular dynamics (MD) simulations as a “computational microscope” to resolve the conformational landscape of the intact HBV capsid at atomic resolution. By modeling the collective motions of millions of atoms, we characterize how local and global structural fluctuations enable the capsid to act as a shapeshifter, adapting its structure to carry out different biological functions. We investigate how conformational variability modulates capsid assembly, governs exposure of host-factor interaction sites, and mediates allosteric communication across the capsid. Further, we demonstrate how mapping the conformational landscape of the capsid provides critical insight for antiviral development. By identifying transient and previously unobserved structural states, we reveal new opportunities for targeting the capsid with small molecules that alter assembly pathways or destabilize the viral particle. Together, this work highlights the power of atomistic simulations to bridge structure, dynamics, and function in complex biomolecular systems, and underscores the importance of conformational ensembles in understanding and targeting viral machinery.