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

Haruna Luz Barazorda-Ccahuana,Sergio Madurga,Miroslava Nedyalkova,Francesc Mas

doi:10.3390/polym13213823

Haruna Luz Barazorda-Ccahuana, Sergio Madurga + Show 2 more

Open Access

https://doi.org/10.3390/polym13213823

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Abstract

(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, H, N1 and H1 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.

Highlights

The COVID-19 pandemic is still an ongoing major health threat for the whole world, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3]
The molecular structure of SARS-CoV-2 Main Protease (Mpro) is a homodimeric structure with approximately 36% of acid/base residues (Asp, Glu, Arg, Lys, His), and almost 8% corresponds to
We have shown that the distance between the residues of the active site and the S1 pocket of the Mpro remained constant during the simulation time, which indicated that the structure of Mpro could not disaggregate at low pH conditions

Summary

Introduction

The COVID-19 pandemic is still an ongoing major health threat for the whole world, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1,2,3]. The proteolytic process was carried out by the SARS-CoV-2 Main Protease (Mpro), a cysteine protease with a catalytic dyad that compromises two principal residues, Cys145 and His41 [17,18,19,20,21,22]. This protein is essential in the life cycle of the virus and is considered a relevant target against the replication of the coronavirus. This covalent acyl-enzyme intermediate is deacylated by an active water molecule releasing the second half of the product [23,24]

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