Exploring the Intrinsic Structural Plasticity and Conformational Dynamics of Human Beta Coronavirus Spike Glycoproteins

The spike (S) glycoprotein of human beta coronaviruses
(HCoVs)
is central to viral entry, receptor engagement, and immune evasion.
Here, we present an in-depth computational analysis of spike conformational
dynamics across HCoVs, with a focus on SARS-CoV-2 and its variants.
Leveraging a large cryo-EM structural ensemble and integrative modeling
approaches, we dissect the intrinsic plasticity and variant-specific
motions of the spike protein. Our results show that, despite substantial
sequence divergence, HCoV spikes retain the ability to sample open
and closed receptor-binding domain (RBD) states. For SARS-CoV-2, a
hinge-like RBD opening motion dominates the conformational landscape,
modulating ACE2 accessibility. Ensemble and single-structure normal
modes revealed conserved dynamic domains and hinge regions and showed
strong agreement with experimental structural transitions. Ligand
binding rather than the D614G mutation was the principal driver of
RBD opening, with multiple open RBDs observed predominantly in ligand-bound
states. Notably, Omicron spike structures favored closed RBDs in the apo form but remained capable of ligand-induced opening.
Dynamical network analysis identified an Omicron-specific remodeling
of interdomain communication, altering the mechanical connectivity
between RBD, NTD, and S2 subunits. Analysis of single-experiment multimodel
cryo-EM data from the Beta variant captured temperature-dependent
metastable states, validating ensemble-based modeling. Finally, hybrid
molecular dynamics simulations successfully reproduced the spike experimentally
observed in conformational space, unlike standard MD. These findings
offer mechanistic insight into spike conformational dynamics, supporting
the design of variant-adapted therapeutics and vaccines.