All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery
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viruses-13-00564.pdf
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10.66 MB
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Author(s)
Pérez-Segura, Carolina
Goh, Boon Chong
Hadden-Perilla, Jodi A.
Date Issued
March 26, 2021
Publisher
Multidisciplinary Digital Publishing Institute
Citation
Viruses 13 (4): 564 (2021)
Version
Final published version
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 antiviral paradigm based on disrupting the timing of genome packaging. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that the compound increases spike flexibility and improves recovery of helical secondary structure in the spike tips. Regions of the capsid-incorporated dimer that undergo correlated motion correspond to established sub-domains that pivot around the central chassis. AT130 alters patterns of correlated motion and other essential dynamics. A new conformational state of the dimer 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 sub-domains. Altogether, results describe a dynamical connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire core protein dimer.
MIT Department
Singapore-MIT Alliance in Research and Technology (SMART)
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Creative Commons Attribution
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DOI of Published Version
https://doi.org/10.3390/v13040564
