Breathing and Tilting: Mesoscale Simulations Illuminate Influenza Glycoprotein Vulnerabilities

Influenza virus has
resurfaced recently from inactivity during
the early stages of the COVID-19 pandemic, raising serious concerns
about the nature and magnitude of future epidemics. The main antigenic
targets of influenza virus are two surface glycoproteins, hemagglutinin
(HA) and neuraminidase (NA). Whereas the structural and dynamical
properties of both glycoproteins have been studied previously, the
understanding of their plasticity in the whole-virion context is fragmented.
Here, we investigate the dynamics of influenza glycoproteins in a
crowded protein environment through mesoscale all-atom molecular dynamics
simulations of two evolutionary-linked glycosylated influenza A whole-virion
models. Our simulations reveal and kinetically characterize three
main molecular motions of influenza glycoproteins: NA head tilting,
HA ectodomain tilting, and HA head breathing. The flexibility of HA
and NA highlights antigenically relevant conformational states, as
well as facilitates the characterization of a novel monoclonal antibody,
derived from convalescent human donor, that binds to the underside
of the NA head. Our work provides previously unappreciated views on
the dynamics of HA and NA, advancing the understanding of their interplay
and suggesting possible strategies for the design of future vaccines
and antivirals against influenza.