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bioRxiv · 10.1101/2021.02.08.430329

All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

Perez Segura, C.·Goh, B. C.·Hadden-Perilla, J. A.
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Abstract

The hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsids ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

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Perez Segura, C., Goh, B. C., Hadden-Perilla, J. A.. 2021-02-08. All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery. https://doi.org/10.1101/2021.02.08.430329

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