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.
Highlights
The COVID-19 pandemic, which is having a devastating social and economic impact worldwide, is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) coronavirus
The D614G mutant shows reduced response of the FPPR and a slower rate of signal propagation to the S20 cleavage site compared to the wild-type protein (Movie 2). These results indicate that the D614G mutation affects the allosteric behaviour and the response to LA of the spike, which may be related to the changes in viral fitness associated with this mutation [78]
The results here further highlight the potential of dynamicalnonequilibrium simulations for identifying pathways of allosteric communication [38,39,40] and suggest that this approach may be useful in analysing mutations and differences in functionally important dynamical behaviour, and possibly different effects of LA, between SARS-CoV-2 spike variants of clinical relevance, such as the Alpha, Beta, Gamma, and Delta, and () Omicron
Summary
The COVID-19 pandemic, which is having a devastating social and economic impact worldwide, is caused by the severe acute respiratory syndrome 2 (SARS-CoV-2) coronavirus. Belongs to the Betacoronavirus genus of the Coronaviridae family which includes pathogenic human coronaviruses that cause SARS severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) [3,4] It initially infects respiratory epithelial cells by binding to the angiotensin-converting 2 enzyme (ACE2) [5,6]. We apply dynamical-nonequilibrium MD simulations [34,35,36,37] to investigate the response of the SARS-CoV2 spike to LA removal We have shown this approach to be effective in identifying structural communication pathways in a variety of proteins, e.g. in identifying a general mechanism of interdomain signal propagation in nicotinic acetylcholine receptors [38,39] and mapping the networks connecting the allosteric and catalytic sites in two clinically relevant b-lactamase enzymes [40]. Running a large number of nonequilibrium simulations allows for the determination of the statistical significance of the structural response observed [37]
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