posted on 2021-04-30, 17:03authored byGennady M. Verkhivker, Luisa Di Paola
Structural
and biochemical studies of the severe acute respiratory
syndrome (SARS)-CoV-2 spike glycoproteins and complexes with highly
potent antibodies have revealed multiple conformation-dependent epitopes
highlighting conformational plasticity of spike proteins and capacity
for eliciting specific binding and broad neutralization responses.
In this study, we used coevolutionary analysis, molecular simulations,
and perturbation-based hierarchical network modeling of the SARS-CoV-2
spike protein complexes with a panel of antibodies targeting distinct
epitopes to explore molecular mechanisms underlying binding-induced
modulation of dynamics and allosteric signaling in the spike proteins.
Through coevolutionary analysis of the SARS-CoV-2 spike proteins,
we identified highly coevolving hotspots and functional clusters that
enable a functional cross-talk between distant allosteric regions
in the SARS-CoV-2 spike complexes with antibodies. Coarse-grained
and all-atom molecular dynamics simulations combined with mutational
sensitivity mapping and perturbation-based profiling of the SARS-CoV-2
receptor-binding domain (RBD) complexes with CR3022 and CB6 antibodies
enabled a detailed validation of the proposed approach and an extensive
quantitative comparison with the experimental structural and deep
mutagenesis scanning data. By combining in silico mutational scanning,
perturbation-based modeling, and network analysis of the SARS-CoV-2
spike trimer complexes with H014, S309, S2M11, and S2E12 antibodies,
we demonstrated that antibodies can incur specific and functionally
relevant changes by modulating allosteric propensities and collective
dynamics of the SARS-CoV-2 spike proteins. The results provide a novel
insight into regulatory mechanisms of SARS-CoV-2 S proteins showing
that antibody-escaping mutations can preferentially target structurally
adaptable energy hotspots and allosteric effector centers that control
functional movements and allosteric communication in the complexes.