PubMed:33501438
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/33501438","sourcedb":"PubMed","sourceid":"33501438","source_url":"https://www.ncbi.nlm.nih.gov/pubmed/33501438","text":"A comparative survey of Betacoronavirus binding dynamics relevant to the functional evolution of the highly transmissible SARS-CoV-2 variant N501Y.\nComparative functional analysis of the binding interactions between various Betacoronavirus mutant strains and their potential multiple human target proteins is crucial for a more complete understanding of zoonotic spillovers of viruses that cause diseases like COVID-19. Here, employing hundreds of replicate sets of nanosecond scale GPU accelerated molecular dynamics simulations, we statistically compare atom motions of ACE2 and CD26 target proteins in both the presence and absence of different strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. In all strains, we demonstrate a universally conserved functional binding signature of the viral RBD with the N-terminal helices of ACE2. We also identify a second more dynamically transient interaction of the viral N501 with the previously confirmed ACE2 K353 and two nearby novel sites, Q325 and the AAQPFLL 386-92 motif. We propose a model of the functional evolution of SARS-type zoonotic spillovers involving both (A) a conserved binding interaction with the N-terminal helices of ACE2 that is preadapted from viral interaction of the Tylonycteris bat coronavirus progenitor strain HKU4 with the SAMLI 291-5 motif in protein CD26 and (B) a more promiscuous and likely more evolvable interaction between viral N501 and the above-mentioned multiple regions of ACE2 that is preadapted from the bat viral interaction at the CD26 SS 333-4 motif. Our recent analysis of the highly transmissible N501Y lineage B.1.1.7 mutation in SARS-CoV-2 also supports this model, identifying a less promiscuous Y501 interaction with ACE2 that favors more stable functional binding with the K353 site 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