Abstract
The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the capsid must be flexible to function; however, capsid structure and dynamics have not been thoroughly characterized in the absence of icosahedral symmetry constraints. Here, all-atom molecular dynamics simulations are leveraged to investigate the capsid without symmetry bias, enabling study of capsid flexibility and its implications for biological function and cryo-EM resolution limits. Simulation results confirm flexibility and reveal a propensity for asymmetric distortion. The capsid's influence on ionic species suggests a mechanism for modulating the display of cellular signals and implicates the capsid's triangular pores as the location of signal exposure. A theoretical image reconstruction performed using simulated conformations indicates how capsid flexibility may limit the resolution of cryo-EM. Overall, the present work provides functional insight beyond what is accessible to experimental methods and raises important considerations regarding asymmetry in structural studies of icosahedral virus capsids.
Highlights
Hepatitis B virus (HBV) is a spherical pararetrovirus that infects hepatocytes
The HBV capsid typically manifests as a T = 4 icosahedral particle, 36 nm in diameter, composed of 120 copies of capsid protein (Cp) homodimer
The capsid carries out important functional roles throughout the HBV infection cycle, assembling to enclose the viral genome, serving as a container for reverse transcription of single-stranded linear pgRNA to circular double-stranded DNA, displaying signals for intracellular trafficking and the binding of viral envelope glycoproteins, and dissociating to release its cargo to the host cell nucleus (Venkatakrishnan and Zlotnick, 2016)
Summary
Hepatitis B virus (HBV) is a spherical pararetrovirus that infects hepatocytes. Despite the availability of a vaccine, around 240 people worldwide suffer from chronic HBV infection (Ott et al, 2012), placing them at risk for severe liver disease, such as cirrhosis and cancer. The capsid carries out important functional roles throughout the HBV infection cycle, assembling to enclose the viral genome (pregenomic RNA, pgRNA), serving as a container for reverse transcription of single-stranded linear pgRNA to circular double-stranded DNA (ds-DNA), displaying signals for intracellular trafficking and the binding of viral envelope glycoproteins, and dissociating to release its cargo to the host cell nucleus (Venkatakrishnan and Zlotnick, 2016). The Cp assembly domain (Cp149) represents the minimum protein length required to achieve self-association of dimers into archetypal capsids (Zlotnick et al, 1996). Atomic models of the assembly domain capsid (4 MDa) have been determined crystallographically via symmetry averaging (Wynne et al, 1999; Bourne et al, 2006; Katen et al, 2013; Venkatakrishnan et al, 2016).
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