In my last post, I showed you the genetic variants at the catalytic site of SARS-CoV-2 Papain-like protease (PLPro) and the predicted effects of those mutations on VIR251-binding.
Next, we wanted to assess the effect of all possible mutations at the sidechains lining the catalytic site of PLPro and how that would affect VIR251-binding. VIR251 is the non-natural amino acid-containing inhibitor that Wioletta Rut and their colleagues have crystalized with PLPro (PDB: 6wx4).
We created an energy matrix where we consider the effect of every possible mutation on the binding of VIR251 with PLPro in table 3. All residues of PLPro catalytic site are included expect Cysteine 111. Cys111 binds covalently with VIR251 and any mutation at this position will be highly detrimental to VIR251 binding.
Table 1. The energy matrix showing the effect of all possible mutations at the SARS-COV-2 PLPro catalytic site and the predicted effect on VIR251 binding. No mutations at Cys111 were considered since it makes the covalent thioether linkage with VIR251 which is essential for its inhibitory mechanism against PLPro. WT column shows the wildtype residue on PLPro x-ray crystal structure 9PDB: 6wx4). The energy unit is kcal/mol. Values above 2 Kcal/mol are highlighted in orange and those below 2 are highlighted in green or neutral color.
We predict that the residues of the rows with green color are not making optimal interactions with VIR251. This is reflected in the very slight and non-significant lowering in ddGbind values of these residues (mutations are stabilizing) and hence the green color. On the other hand, the sidechains whose mutations are shown in orange are likely the positions where PLPro would better interact with VIR251. As a result, the mutations of those sidechains are predicted to penalize inhibitor-binding significantly and hence the orange color.
This post marks the end of PLPro analysis. To see the full report on PLPro, please refer to my Zenodo report.
Please contact me via the “Leave a comment” link at the top of this post. Stay Tuned for more updates on this project!