Computational Methods to unveil the Structural Bases for the recognition of SARS-CoV-2 by Human Nicotinic Acetylcholine Receptors

The novel pathogen SARS-CoV-2 has caused the global pandemic of Covid-19. The hypothesis of this study is that Nicotinic Acetylcholine Receptors (nAChRs) are involved in SARS-CoV-2 infection, explaining the hyper-inflammatory characteristics observed in a subset of Covid-19 patients. nAChRs represent specific receptors for a wide variety of toxins and have been proposed to serve as receptors for Rabies Virus (RABV) and Human Immunodeficiency Virus (HIV) as well, based on sequence homology with the so called “toxic loop” of α-bungarotoxin. Sequence similarities between a motif found in SARS-CoV-2 S protein and in snake neurotoxins, as well as RABV neurotoxin-like region, HIV-1 gp120 and α-conotoxin from Conus geographus, highlights the existence of a correlation between these proteins’ functional sites. In this study, in silico procedures were used to determine SARS-CoV-2 S protein structure-function relationships, revealing the presence of features characteristic of the “toxic loop” known to bind nAChRs and their involvement in the S protein-nAChR interaction. Our results suggest that a polybasic sequence-carrying motif found in SARS-CoV-2 S protein could be involved in the binding, in particular underling the role of Arg685 in the interaction with the receptor.