The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
Comput Struct Biotechnol J
; 20: 139-147, 2022.
Article
in English
| MEDLINE | ID: covidwho-1568616
Preprint
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This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
See preprint
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.
ACE2, angiotensin-converting 2 enzyme; CD, connector domain; CH, central helix; FA, fatty acid; FP, fusion peptide; FPPR, fusion-peptide proximal region; HR1, heptad repeat 1; LA, Linoleic acid; MD, Molecular dynamics; MERS, middle east respiratory syndrome; NTD, N-terminal domain; RBD, receptor binding domain; RBM, receptor-binding motif; RMB, receptor binding motif; SARS, severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome 2
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Prognostic study
Topics:
Variants
Language:
English
Journal:
Comput Struct Biotechnol J
Year:
2022
Document Type:
Article
Affiliation country:
J.csbj.2021.12.011
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