RT Journal Article SR Electronic T1 Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.07.16.206680 DO 10.1101/2020.07.16.206680 A1 F. Oliveira, A. Sofia A1 Ibarra, Amaurys Avila A1 Bermudez, Isabel A1 Casalino, Lorenzo A1 Gaieb, Zied A1 Shoemark, Deborah K. A1 Gallagher, Timothy A1 Sessions, Richard B. A1 Amaro, Rommie E. A1 Mulholland, Adrian J. YR 2020 UL http://biorxiv.org/content/early/2020/09/14/2020.07.16.206680.abstract AB Changeux et al. recently suggested that the SARS-CoV-2 spike (S) protein may interact with nicotinic acetylcholine receptors (nAChRs). Such interactions may be involved in pathology and infectivity. Here, we use molecular simulations of validated atomically detailed structures of nAChRs, and of the S protein, to investigate this ‘nicotinic hypothesis’. We examine the binding of the Y674-R685 loop of the S protein to three nAChRs, namely the human α4β2 and α7 subtypes and the muscle-like αβγd receptor from Tetronarce californica. Our results indicate that Y674-R685 has affinity for nAChRs and the region responsible for binding contains the PRRA motif, a four-residue insertion not found in other SARS-like coronaviruses. In particular, R682 has a key role in the stabilisation of the complexes as it forms interactions with loops A, B and C in the receptor’s binding pocket. The conformational behaviour of the bound Y674-R685 region is highly dependent on the receptor subtype, adopting extended conformations in the α4β2 and α7 complexes and more compact ones when bound to the muscle-like receptor. In the α4β2 and αβγd complexes, the interaction of Y674-R685 with the receptors forces the loop C region to adopt an open conformation similar to other known nAChR antagonists. In contrast, in the α7 complex, Y674-R685 penetrates deeply into the binding pocket where it forms interactions with the residues lining the aromatic box, namely with TrpB, TyrC1 and TyrC2. Estimates of binding energy suggest that Y674-R685 forms stable complexes with all three nAChR subtypes. Analyses of the simulations of the full-length S protein show that the Y674-R685 region is accessible for binding, and suggest a potential binding orientation of the S protein with nAChRs.Competing Interest StatementThe authors have declared no competing interest.