Comparative protein structure network analysis on 3CL(pro) from SARS‐CoV‐1 and SARS‐CoV‐2

Lata, Surabhi; Akif, Mohd.

The main protease M(pro), 3CL(pro) is an important target from coronaviruses. In spite of having 96% sequence identity among M(pros) from SARS‐CoV‐1 and SARS‐CoV‐2; the inhibitors used to block the activity of SARS‐CoV‐1 M(pro) so far, were found to have differential inhibitory effect on M(pro) of SARS‐CoV‐2. The possible reason could be due to the difference of few amino acids among the peptidases. Since, overall 3‐D crystallographic structure of M(pro) from SARS‐CoV‐1 and SARS‐CoV‐2 is quite similar and mapping a subtle structural variation is seemingly impossible. Hence, we have attempted to study a structural comparison of SARS‐CoV‐1 and SARS‐CoV‐2 M(pro) in apo and inhibitor bound states using protein structure network (PSN) based approach at contacts level. The comparative PSNs analysis of apo M(pros) from SARS‐CoV‐1 and SARS‐CoV‐2 uncovers small but significant local changes occurring near the active site region and distributed throughout the structure. Additionally, we have shown how inhibitor binding perturbs the PSG and the communication pathways in M(pros). Moreover, we have also investigated the network connectivity on the quaternary structure of M(pro) and identified critical residue pairs for complex formation using three centrality measurement parameters along with the modularity analysis. Taken together, these results on the comparative PSN provide an insight into conformational changes that may be used as an additional guidance towards specific drug development.