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(1) Background: Main Protease (Mpro) is an attractive therapeutic target that acts in the replication and transcription of the SARS-CoV-2 coronavirus. Mpro is rich in residues exposed to protonation/deprotonation changes which could affect its enzymatic function. This work aimed to explore the effect of the protonation/deprotonation states of Mpro at different pHs using computational techniques. (2) Methods: The different distribution charges were obtained in all the evaluated pHs by the Semi-Grand Canonical Monte Carlo (SGCMC) method. A set of Molecular Dynamics (MD) simulations was performed to consider the different protonation/deprotonation during 250 ns, verifying the structural stability of Mpro at different pHs. (3) Results: The present findings demonstrate that active site residues and residues that allow Mpro dimerisation was not affected by pH changes. However, Mpro substrate-binding residues were altered at low pHs, allowing the increased pocket volume. Additionally, the results of the solvent distribution around S    γ    , H    γ    , N    δ    1 and H    δ    1 atoms of the catalytic residues Cys145 and His41 showed a low and high-water affinity at acidic pH, respectively. It which could be crucial in the catalytic mechanism of SARS-CoV-2 Mpro at low pHs. Moreover, we analysed the docking interactions of PF-00835231 from Pfizer in the preclinical phase, which shows excellent affinity with the Mpro at different pHs. (4) Conclusion: Overall, these findings indicate that SARS-CoV-2 Mpro is highly stable at acidic pH conditions, and this inhibitor could have a desirable function at this condition.

Unveiling the Effect of Low pH on the SARS-CoV-2 Main Protease by Molecular Dynamics Simulations