Zhaleh Ghaemi, Martin Gruebele, and Emad Tajkhorshid.
Molecular mechanism of capsid disassembly in hepatitis B virus.
Proceedings of the National Academy of Sciences, USA,
118:e2102530118, 2021.
GHAE2021-ET
The disassembly of a viral capsid leading to the release of its
genetic material into the host cell is a fundamental step in viral
infection. In hepatitis B virus (HBV), the capsid con- sists of
identical protein monomers that dimerize and then arrange themselves
into pentamers or hexamers on the capsid surface. By applying
atomistic molecular dynamics simulation to an entire solvated HBV
capsid subjected to a uniform mechanical stress protocol, we monitor
the capsid-disassembly process and analyze the process down to the
level of individual amino acids in 20 independent simulation
replicas. The strain of an isotropic external force, combined with
structural fluctuations, causes structurally heterogeneous cracks to
appear in the HBV capsid. Analysis of the monomer–monomer interfaces
reveals that, in contrast to the expectation from purely mechanical
considerations, the cracks mainly occur within hexameric sites,
whereas pentameric sites remain largely intact. Only a small subset
of the capsid protein monomers, different in each simulation, are
engaged in each instance of disassembly. We identify specific
residues whose interactions are most readily lost during disassembly;
R127, I139, Y132, N136, A137, and V149 are among the hot spots at the
interfaces between dimers that lie within hexamers, leading to
disassembly. The majority of these hot-spot residues are conserved by
evolution, hinting to their importance for disassembly by avoiding
overstabilization of capsids.
