Allosteric modulation by the fatty acid site in the glycosylated SARS-CoV-2 spike
Year: 2024
Type: preprint
Abstract: The trimeric spike protein plays an essential role in the SARS-CoV-2 virus lifecycle, facilitating virus entry through binding to the cellular receptor angiotensin-converting enzyme 2 (ACE2) and mediating viral and host membrane fusion. The SARS-CoV-2 spike contains an allosteric fatty acid (FA) binding site at the interface between two neighbouring receptor-binding domains. This site, also found in some other coronaviruses, binds free fatty acids such as linoleic and oleic acid, and other small molecules. Understanding allostery and how this site modulates the behaviour of different regions in this protein could potentiate the development of promising alternative strategies for new coronavirus therapies. Here, we apply dynamical nonequilibrium molecular dynamics (D-NEMD) simulations to investigate allosteric effects and identify the communication pathways in the fully glycosylated spike in the original SARS-CoV-2 ancestral variant. The results reveal the allosteric networks that connect the FA site to important functional regions of the protein, including some more than 40 Å away. These regions include the receptor binding motif, an antigenic supersite in the N-terminal domain, the furin cleavage site, the regions surrounding the fusion peptide and a second 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 connection between different allosteric sites. Notably, 65% of amino acid substitutions, deletions and insertions in the Alpha, Beta, Delta, Gamma and Omicron variants map onto or close to the identified allosteric pathways.
Source: eLife
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation, BrisSynBio: Bristol Centre for Synthetic Biology, The UK High-End Computing Consortium for Biomolecular Simulation, Inquire: Software for real-time analysis of binding, Commercialisation of VR for biomolecular design, Predictive multiscale free energy simulations of hybrid transition metal catalysts, The UK High-End Computing Consortium for Biomolecular Simulation, G3429295937, 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, 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, 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, The UK High-End Computing Consortium for Biomolecular Simulation, G968217139
OpenAlex ID: W4400950266