tetano
Editor, Senior Moderator
J Chem Inf Model
. 2025 Jul 17.
doi: 10.1021/acs.jcim.5c00990. Online ahead of print. Exploring the Intrinsic Structural Plasticity and Conformational Dynamics of Human Beta Coronavirus Spike Glycoproteins
Yago Ferreira E Silva[SUP] 1 2 [/SUP], Harold Hilarion Fokoue[SUP] 1 [/SUP], Paulo Ricardo Batista[SUP] 1 2 [/SUP]
Affiliations
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.
. 2025 Jul 17.
doi: 10.1021/acs.jcim.5c00990. Online ahead of print. Exploring the Intrinsic Structural Plasticity and Conformational Dynamics of Human Beta Coronavirus Spike Glycoproteins
Yago Ferreira E Silva[SUP] 1 2 [/SUP], Harold Hilarion Fokoue[SUP] 1 [/SUP], Paulo Ricardo Batista[SUP] 1 2 [/SUP]
Affiliations
- PMID: 40673918
- DOI: 10.1021/acs.jcim.5c00990
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.