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The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour

Authors
  • Sofia F. Oliveira, A.
  • Shoemark, Deborah K.
  • Avila Ibarra, Amaurys
  • Davidson, Andrew D.
  • Berger, Imre
  • Schaffitzel, Christiane
  • Mulholland, Adrian J.
Type
Published Article
Journal
Computational and Structural Biotechnology Journal
Publisher
Elsevier
Publication Date
Dec 11, 2021
Volume
20
Pages
139–147
Identifiers
DOI: 10.1016/j.csbj.2021.12.011
PMID: 34934478
PMCID: PMC8670790
Source
PubMed Central
Keywords
Disciplines
  • Communications
License
Unknown

Abstract

The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. Simulations of the D614G mutant show differences in behaviour between these clinical variants of the spike: the D614G mutant shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.

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