Role of RNA Guanine Quadruplexes in Favoring the Dimerization of SARS Unique Domain in Coronaviruses

Cécilia Hognon; Tom Miclot; Cristina Garcia Iriepa; Antonio Francés-Monerris; Stephanie Grandemange; Alessio Terenzi; Marco Marazzi; Giampaolo Barone; Antonio Monari

. CC-BY-NC-ND 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.07.029447 doi: bioRxiv preprint Interestingly, the specific interaction patterns between G4 and the protein are different between the two binding modes, providing an extremely important different behavior. Indeed, the main driving force for the dimeric-like binding mode is the presence of extended electrostatic interactions between the negatively charged RNA backbone and the highly positive interaction pockets of the SUD complex. As a matter of fact, eleven Lys resides in the interaction pocket (shown in green in Figure 3a ) allowing persistent salt-bridges and hydrogen-bonds with the RNA phosphates. This finding is evidenced by the radial distribution function (RDF) between these positively charged lysine side chains and the negatively charged phosphate oxygen atoms of G4 (depicted in dark blue in Figure 3b ), which shows a very intense and sharp peak at around 2 Ã… ( Figure 3a ). Interestingly, a secondary peak in the RDF is also observed at 3.5 Ã…, probably defining The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.04.07.029447 doi: bioRxiv preprint a second layer of interaction patterns that should contribute to the overall stabilization of the binding. Conversely, the monomeric mode is not driven by electrostatic interactions and involves mainly the terminal uracil moieties and the top guanine leaflet instead of the phosphate backbone of G4. As shown in Figure 3b , hydrophobic dispersion interactions emerge through the action of a triad of amino acids, namely Ser236, Leu237, and Asn238, that position themselves on top of the terminal leaflet also interacting with the peripheral uracil nucleobases, in a mode strongly resembling the top-binding experienced by a number of G4 drugs. [50] [51] [52] This is nicely confirmed by the analysis of the time series of the distance between the a-carbon of these amino acids and the nearby guanine that readily drops at around 5 Ã… and stays remarkably stable all along the MD.