Structural analysis of SARS-CoV-2 and prediction of the human interactome

Andrea Vandelli; Michele Monti; Edoardo Milanetti; Riccardo Delli Ponti; Gian Gaetano Tartaglia

In order to obtain insights on how the virus replicates in human cells, we predicted SARS-CoV-2 184 interactions with the whole RNA-binding human proteome. Following a protocol to study structural 185 conservation in viruses 13 , we first divided the Wuhan sequence in 30 fragments of 1000 nucleotides 186 each moving from the 5' to 3' and then calculated the protein-RNA interactions of each fragment 187 with catRAPID omics (3340 canonical and putative RNA-binding proteins, or RBPs, for a total 188 102000 interactions) 18 . Proteins such as Polypyrimidine tract-binding protein 1 PTBP1 (Uniprot 189 P26599) showed the highest interaction propensity (or Z-score; Materials and Methods) at the 5' 190 while others such as Heterogeneous nuclear ribonucleoprotein Q HNRNPQ (O60506) showed the 191 highest interaction propensity at the 3', in agreement with previous studies on coronaviruses (Fig. 192 4A) 35 . 193 194 For each fragment, we predicted the most significant interactions by filtering according to the Z 195 score. We used three different thresholds in ascending order of stringency: Z ³ 1.50, 1.75 and 2 196 respectively and we removed from the list the proteins that were predicted to interact promiscuously 197 with more than one fragment. Fragment 1 corresponds to the 5' and is the most contacted by RBPs 198 (around 120 with Z³2 high-confidence interactions; Fig. 4B ), which is in agreement with the 199 observation that highly structured regions attract a large number of proteins 14 . Indeed, the 5' 200 contains multiple stem loop structures that control RNA replication and transcription 36,37 . By 201 contrast, the 3' and fragment 23 (Spike S), which are still structured but to a lesser extent, attract 202 fewer proteins (10 and 5, respectively), while fragment 20 (between orf1ab and Spike S) that is 203 predicted to be unstructured, does not have binding partners. 204 author/funder. All rights reserved. No reuse allowed without permission.