Molecular Insight into the Hepatitis B Virus: Coarse-Grained Simulations of the Envelope-Capsid Complex.

We present the first molecular dynamics simulation of a hepatitis B virus (HBV) particle, encompassing both the icosahedral capsid and the surrounding lipid-protein envelope. Using a chemically realistic coarse-grained model with the SPICA force field, we simulated HBV envelope systems with and without the capsid alongside a pure lipid vesicle for comparison. Our simulations accurately reproduce experimental electron density profiles and reveal stable molecular interactions between capsid spikes and transmembrane regions of S proteins. These interactions involve experimentally validated contact sites as well as previously unrecognized residues that are critical for envelope-capsid association. We also found that lipid diffusion within the envelope is more than five times slower than in a simple vesicle and is further reduced by the presence of the capsid. This highlights the strong protein-mediated modulation of the membrane dynamics. This study provides the first molecular-level view of the HBV capsid-envelope complex and establishes a foundation for more complete HBV models that will include M/L proteins, nucleic acids, and diverse lipid components.