Candidate Binding Sites for Allosteric Inhibition of the SARS-CoV-2 Main Protease from the Analysis of Large-Scale Molecular Dynamics Simulations

We analyzed a 100 mu s MD trajectory of the SARS-CoV-2 main protease by a non-parametric data analysis approach which allows characterizing a free energy landscape as a simultaneous function of hundreds of variables. We identified several conformations that, when visited by the dynamics, are stable for several hundred nanoseconds. We explicitly characterize and describe these metastable states. In some of these configurations, the catalytic dyad is less accessible. Stabilizing them by a suitable binder could lead to an inhibition of the enzymatic activity. In our analysis we keep track of relevant contacts between residues which are selectively broken or formed in the states. Some of these contacts are formed by residues which are far from the catalytic dyad and are accessible to the solvent. Based on this analysis we propose some relevant contact patterns and three possible binding sites which could be targeted to achieve allosteric inhibition.

Automated summary

Through molecular dynamics trajectory analysis, we identified several stable conformations within hundreds of nanoseconds and characterized the properties of these metastable states. We described conformations where the catalytic dyad is less accessible and proposed the potential inhibition of enzymatic activity by stabilizing them with a suitable binder. We also tracked relevant contacts selectively broken or formed between residues in different states.