Year: 2025
Type: article
Abstract: The spike protein is essential to the SARS-CoV-2 virus life cycle, facilitating virus entry and mediating viral-host membrane fusion. The spike contains a fatty acid (FA) binding site between every two neighbouring receptor-binding domains. This site is coupled to key regions in the protein, but the impact of glycans on these allosteric effects has not been investigated. Using dynamical nonequilibrium molecular dynamics (D-NEMD) simulations, we explore the allosteric effects of the FA site in the fully glycosylated spike of the SARS-CoV-2 ancestral variant. Our results identify the allosteric networks connecting the FA site to functionally important regions in the protein, including the receptor-binding motif, an antigenic supersite in the N-terminal domain, the fusion peptide region, and another allosteric site known to bind heme and biliverdin. The networks identified here highlight the complexity of the allosteric modulation in this protein and reveal a striking and unexpected link between different allosteric sites. Comparison of the FA site connections from D-NEMD in the glycosylated and non-glycosylated spike revealed that glycans do not qualitatively change the internal allosteric pathways but can facilitate the transmission of the structural changes within and between subunits.
Source: eLife
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Oracle, Wellcome Trust, American Society of Forensic Odontology, UK Research and Innovation, Moores Cancer Center, UC San Diego Health, European Commission, University of Bristol, Directorate for Biological Sciences, Medical Research Council, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, European Research Council
Awards: G1084281444, Structure and Mechanism of Key Nonsense-Mediated mRNA Decay Factor Complexes, Expanding the capabilities and use of the South West Regional Facility for High-Resolution Electron Cryo-microscopy, Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation, BrisSynBio: Bristol Centre for Synthetic Biology, G2109111079, The UK High-End Computing Consortium for Biomolecular Simulation, G2272451908, Novel platforms to develop polyspecifically-effective, safe, affordable and thermostable monoclonal camelid VHH nanobodies to treat snake venom-induced necrosis in India and sub-Saharan Africa, Inquire: Software for real-time analysis of binding, Commercialisation of VR for biomolecular design, Predictive multiscale free energy simulations of hybrid transition metal catalysts, G339059223, The UK High-End Computing Consortium for Biomolecular Simulation, G3429295937, G3878006490, G4114594511, G4310967859, G434337789, G4560633741, CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface, CCP-BioSim: Biomolecular simulation at the life sciences interface, The G2P2 virology consortium: keeping pace with SARS-CoV-2 variants, providing evidence to vaccine policy, and building agility for the next pandemic, Combined experimental and computational investigations of a nucleophilic displacement reaction with a hydride leaving group, Creating and comprehending the circuitry of life: precise biomolecular design of multi-centre redox enzymes for a synthetic metabolism, G2P-UK; A National Virology Consortium to address phenotypic consequences of SARSCoV-2 genomic variation, G6085025897, G6122222817, G6144325969, Adaptive Multi-Resolution Massively-Multicore Hybrid Dynamics, G6505985298, Combined quantum mechanics/molecular mechanics (QM/MM) Monte Carlo free energy simulations: a feasibility study, Predicting drug-target binding kinetics through multiscale simulations, BEORHN: Bacterial Enzymatic Oxidation of Reactive Hydroxylamine in Nitrification via Combined Structural Biology and Molecular Simulation, Nicotinic Ligand Development to Target Smoking Cessation and Gain a Molecular Level Understanding of Partial Agonism, Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription., BristolBridge: Bridging the Gaps between the Engineering and Physical Sciences and Antimicrobial Resistance, Dynamical-nonequilibrium simulations: an emerging approach to study time-dependent structural changes in proteins, Multiscale Ensemble Computing for Modelling Biological Catalysts, Computational biochemistry: predictive modelling for biology and medicine, Unlocking the structure, mechanism and cellular assembly of key multiprotein complexes in human gene transcription., South West Regional Facility for High-Resolution Electron Cryo-Microscopy, G8415457339, The UK High-End Computing Consortium for Biomolecular Simulation, Structure and Mechanism of Key Nonsense-Mediated mRNA Decay Factor Complexes, G968217139
OpenAlex ID: W4409331037