Biophysical characterization of the SARS-CoV2 spike protein binding with the ACE2 receptor explains increased COVID-19 pathogenesis

Ratul Chowdhury; Costas D Maranas

We have used experimentally determined coordinates of SARS-CoV-1 and SARS-CoV-2 in complex with ACE2 (PDB accessions: 6ACG 3 and 6LZG -www.rcsb.org/structure/6lzg, respectively). OC43 RBD was isolated from the crystal structure of the whole OC43 spike (PDB: 6OHW 10 ). Similarly, unbound ATR1 structure (PDB: 4YAY 11 ) was also separately downloaded and docked against ACE2 using proteinprotein docking scripts from Z-DOCK 3.0 12 . ZDOCK uses pairwise shape-complementarity, The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.30.015891 doi: bioRxiv preprint electrostatics, and implicit solvation terms in scoring the docked poses. Implicit solvation treats the water as a dielectric continuum. The rotational sampling interval was set to 10°. Clustering of the docked poses were done at an 8 Å cutoff. Subsequently, PyRosetta 13 scripts were written to rank and identify the most stable complexes from each cluster which were then energy-minimized and re-ranked. Finally, the complex which ranked high in stability and binding scores was chosen as the model. An alanine scan was again performed using PyRosetta scripts, where the computational models of the alanine variants were first generated, energy minimized, and ACE2 binding scores computed. The ACE2 interface definitions for each binding partner (RBDs and ATR1) were obtained by feeding the energy minimized proteinprotein complexes through the find_contacts module of OptMAVEn-2.0 14 .