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All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery
Carolina Pérez-Segura 1 , Boon Chong Goh 2 , Jodi A Hadden-Perilla 1
Affiliations
Affiliations
1
Department of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA.
2
Antimicrobial Resistance Interdisciplinary Research Group, Singapore-Massachusetts Institute of Technology Alliance for Research and Technology Centre, Singapore 138602, Singapore.
PMID: 33810481 DOI: 10.3390/v13040564
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.
Keywords: AT130; CpAM; HBV; core protein allosteric modulator; hepatitis B virus; molecular dynamics simulations; phenylpropenamide; physical virology, computational virology; virus capsid.
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