Topological analysis of SARS CoV-2 main protease

Abstract

There is an urgent necessity of effective medication against severe acute respiratory syndrome coronavirus 2 (SARS CoV-2), which is producing the COVID-19 pandemic across the world. Its main protease (M^pro) represents an attractive pharmacological target due to its involvement in essential viral functions. The crystal structure of free M^pro shows a large structural resemblance with the main protease of SARS CoV (nowadays known as SARS CoV-1). Here, we report that average SARS CoV-2 M^pro is 1900% more sensitive than SARS CoV-1 M^pro in transmitting tiny structural changes across the whole protein through long-range interactions. The largest sensitivity of M^pro to structural perturbations is located exactly around the catalytic site Cys-145 and coincides with the binding site of strong inhibitors. These findings, based on a simplified representation of the protein as a residue network, may help in designing potent inhibitors of SARS CoV-2 M^pro.

FIG. 1.

Cartoon representation (left) of the M${}^{\text{pro}}$ of SARS CoV-2 ($\text{PDB}=\text{6Y2E}$) and the corresponding protein residue network (right).

FIG. 2.

Example to illustrate the sensitivity of the topological measures to structural changes in protein residue networks (see the text for explanations). (a) A graph with two chordless cycles of 6 nodes. (b) A graph with a chordless cycle of 5 nodes and another of 7 nodes.

FIG. 3.

Plot of subgraph centrality (a)–(c) as well as LR subgraph centrality (d)–(f) of the amino acid residues for the M${}^{\text{pro}}$ of SARS CoV-1 (a) and (d), SARS CoV-2 (b) and (e), and the difference between them (c) and (f).

FIG. 4.

Illustration of the subgraph (a) and (c) and LR subgraph (b) and (d) centralities of the amino acid residues of the chain A of SARS CoV-1 M${}^{\text{pro}}$ of (top) and of SARS CoV-2 (bottom). The size of the nodes is proportional to the corresponding centrality normalized to its largest value in the protease analyzed. The colors also correspond to the same values in the jet color code, with red for higher values and blue for smaller values.

FIG. 5.

Illustration of the 22 amino acids that display the largest difference in the LR subgraph centrality in a representative M${}^{\text{pro}}$ of SARS CoV-2 (6Y2E) in relation to one of SARS CoV-1 (2BX4). The radius of the nodes is proportional to the difference in the LR subgraph centrality between the two proteases. The catalytic site Cys-145 is pointed to with an arrow. The size of the nodes is proportional to the corresponding centrality normalized to its largest value in the protease analyzed. The colors also correspond to the same values in the jet color code, with red for higher values and blue for smaller values.

FIG. 6.

Difference between communicabilities (a) and the LR communicability (b) between pairs of amino acids in the averaged structures of M${}^{\text{pro}}$ of SARS CoV-2 in relation to that of SARS CoV-1.

FIG. 7.

Illustration of the 22 amino acids with the largest values of the LR subgraph centrality in 6M0K (a), 6LZE (b), and 6Y2G (c). The residues are connected if they are at no more than 7.0 Å. The color bar and the radius of the nodes indicate the values of $Z_{ii}$.