Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.11.293258v1?rss=1 Authors: Rynkiewicz, P. X., Babbitt, G. A., Cui, F. X., Hudson, A. O., Lynch, M. L. Abstract: Comparative functional analysis of the binding interactions between various betacoronavirus strains and their potential human target proteins, such as ACE1, ACE2 and CD26, is critical to our future understanding and combating of COVID-19. Here, employing large replicate sets of GPU accelerated molecular dynamics simulations, we statistically compare atom fluctuations of the known human target proteins in both the presence and absence of different strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. We identify a common interaction site between the N-terminal helices of ACE2 and the viral RBD in all strains (hCoV-OC43, hCoV-HKU1, MERS-CoV, SARS-CoV1, and SARS-CoV-2) and a second more dynamically complex RBD interaction site involving the ACE2 amino acid sites K353, Q325, and a novel motif, AAQPFLL (386-392) in the more recent cross-species spillovers (i.e. absent in hCoV-OC43). We use computational mutagenesis to further confirm the functional relevance of these sites. We propose a "one touch/two touch" model of viral evolution potentially involved in functionally facilitating binding interactions in zoonotic spillovers. We also observe these two touch sites governing RBD binding activity in simulations on hybrid models of the suspected viral progenitor, batCoV-HKU4, interacting with both the human SARS target, ACE2, and the human MERS target, CD26. Lastly, we confirm that the presence of a common hypertension drug (lisinopril) within the target site of SARS-CoV-2 bound models of ACE1 and ACE2 acts to enhance the RBD interactions at the same key sites in our proposed model. In the near future, we recommend that our comparative computational analysis identifying these key viral RBD-ACE2 binding interactions be supplemented with comparative studies of site-directed mutagenesis in order to screen for current and future coronavirus strains at high risk of zoonotic transmission to humans. Copy rights belong to original authors. Visit the link for more info