Mesoscale simulations illuminate the functional interplay and the vulnerabilities of influenza virus glycoproteins.

Abstract

Influenza A virus (IAV) has menacingly resurfaced during the last flu season, posing an additional threat to public health as it started overlapping with the ongoing COVID-19 pandemic. This concerning scenario foregrounds the urgency of a universal influenza vaccine that is not affected by the antigenic drift and would put an end to the flu. The main targets are the two principal membrane glycoproteins, hemagglutinin (HA) and neuraminidase (NA), whose functional balance is at the basis of IAV virulence and transmissibility. Here, we have used the ‘computational microscope’ to provide unseen views of the glycoprotein interplay and dynamics. By integrating experimental structural data with computational approaches, we have built two massive models of the whole H1N1 IAV accounting for different strains and glycosylation profiles. Mesoscale, all-atom molecular dynamics simulations of these systems tallying ∼160 million atoms have handed over unique insights into the glycoprotein conformational dynamics that would not have been accessible through individual protein simulations. On top of deciphering the glycoprotein interplay and cooperativity, we have characterized the functional motions of HA and NA in a crowded, realistic environment, shedding light on the recondite viral egress process. Interestingly, these motions are found to transiently expose cryptic epitopes on the NA and HA surface, offering new opportunities for vaccine development.