Flexibility and intrinsic disorder are conserved features of hepatitis C virus E2 glycoprotein

• Published in: PLoS computational biology Vol. 16; no. 2; p. e1007710
• Main Authors: Stejskal, Lenka, Lees, William D, Moss, David S, Palor, Machaela, Bingham, Richard J, Shepherd, Adrian J, Grove, Joe
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 28-02-2020; Public Library of Science (PLoS)
• Subjects: Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; Antigens; Biology and Life Sciences; Cell surface; Computer applications; Computer Simulation; Correlation analysis; Divergence; Epitopes - immunology; Flexibility; Glycoprotein E2; Glycoproteins; Glycosylation; HEK293 Cells; Hepatitis; Hepatitis C; Hepatitis C - virology; Hepatitis C virus; Humans; Immunoglobulins; Infections; Machinery; Medicine and health sciences; Molecular biology; Molecular dynamics; Molecular Dynamics Simulation; Physical Sciences; Protein Binding; Protein Domains; Proteins; Receptors; Research and Analysis Methods; Scattering, Radiation; Small angle X ray scattering; Strains (organisms); Vaccine development; Vaccines; Viral Envelope Proteins - chemistry; Virus Internalization; Viruses; X-ray scattering; X-Rays; United Kingdom > UK
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1007710

The glycoproteins of hepatitis C virus, E1E2, are unlike any other viral fusion machinery yet described, and are the current focus of immunogen design in HCV vaccine development; thus, making E1E2 both scientifically and medically important. We used pre-existing, but fragmentary, structures to model a complete ectodomain of the major glycoprotein E2 from three strains of HCV. We then performed molecular dynamic simulations to explore the conformational landscape of E2, revealing a number of important features. Despite high sequence divergence, and subtle differences in the models, E2 from different strains behave similarly, possessing a stable core flanked by highly flexible regions, some of which perform essential functions such as receptor binding. Comparison with sequence data suggest that this consistent behaviour is conferred by a network of conserved residues that act as hinge and anchor points throughout E2. The variable regions (HVR-1, HVR-2 and VR-3) exhibit particularly high flexibility, and bioinformatic analysis suggests that HVR-1 is a putative intrinsically disordered protein region. Dynamic cross-correlation analyses demonstrate intramolecular communication and suggest that specific regions, such as HVR-1, can exert influence throughout E2. To support our computational approach we performed small-angle X-ray scattering with purified E2 ectodomain; this data was consistent with our MD experiments, suggesting a compact globular core with peripheral flexible regions. This work captures the dynamic behaviour of E2 and has direct relevance to the interaction of HCV with cell-surface receptors and neutralising antibodies.