Graphical 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.
【저자키워드】 RBD, receptor binding domain, MD, molecular dynamics, SARS, Severe acute respiratory syndrome, MERS, Middle East respiratory syndrome, NTD, N-terminal domain, LA, linoleic acid, RBM, receptor-binding motif, FA, fatty acid, SARS-CoV-2, severe acute respiratory syndrome 2, RMB, receptor binding motif, FP, fusion peptide, FPPR, fusion-peptide proximal region, HR1, heptad repeat 1, CH, central helix, CD, connector domain, ACE2, angiotensin-converting 2 enzyme, 【초록키워드】 Mutation, variant, binding site, Molecular dynamics simulation, Protein, Simulation, Region, furin cleavage site, SARS-CoV-2 spike protein, Genetic variation, D614G, membrane fusion, mutant, receptor-binding motif, change, binding, Ligand, Contact, host cell, Science, Abstract, removal, binding pocket, human ACE2 receptor, motif, Affect, regions, Alter, identify, significantly, transmitted, modulate, conformational, fatty, the SARS-CoV-2 virus, 【제목키워드】 Spike protein, motif, functional, modulate, fatty, the SARS-CoV-2,