Physiological models to study the effect of molecular crowding on multi-drug bound proteins: insights from SARS-CoV-2 main protease

Abstract

Molecular Dynamics simulations are often used in drug design. However, such simulations do not account for the physiological environment of the receptor; hence overlook its impact on biomolecular interactions. To address this lacuna, we identified three objectives to pursue – develop models of physiological environment, study a drug-receptor complex in such environments, and identify methods to analyze these complicated simulations. Two novel physiological models were developed and studied. The first, called ‘m10’, comprises of 10 of the most abundant cytoplasmic metabolites at physiological concentrations. The second, called ‘phy’, supplements m10 with an additional crowder protein to elicit macromolecular crowding effect. The main protease (M^pro) of SARS-CoV-2, being essential for viral replication, is an attractive drug target for COVID-19. Hence, we chose M^pro docked with multiple drugs as our model drug-receptor system. With a plethora of compounds, physiological systems can be exceedingly large and complex. A novel Spark-based software (SparkTraj) was developed to rapidly analyze non-specific contacts and water interactions. Our study shows that crowding enhances the difference in the dynamics of apo- vs drug-bound complexes. Metabolites, at times as a cluster, were seen interacting with the protease, drugs, and binding sites in drug-free receptor. Except one that crawled to an adjacent pocket in phy, the drugs remained in their respective pockets in all simulations. Given these observations, we hope that the models and approach presented here would help the optimization, evaluation, and selection of potential drugs. Generic biomolecular dynamics could also benefit from such models and tools.

Communicated by Ramaswamy H. Sarma

Keywords:

• Human SARS-CoV-2
• molecular crowding
• molecular dynamics

Acknowledgements

The authors thank Mr. Zahoor Ahmad Bhat (Jamia Millia Islamia, New Delhi) for providing structure of M^pro (dimer)-drug complex. Dr. Muneendra Ojha (IIIT-NR) and Mr. Suprateek Chatterjee (IIIT-A) are acknowledged for proofreading the manuscript. We would like to thank the referees and the editor for helping us to improve the manuscript in terms of presentation and quality. The Central Computing Facility and Indian Institute of Information Technology - Allahabad are acknowledged for the computational facilities and support.

Disclosure statement

No potential conflict of interest was reported by the authors.

Funding

The author(s) reported there is no funding associated with the work featured in this article.

Notes

1 Except for inter-chain sites.

2 BG1s had insignificant contacts and hence not shown.

3 R2 never disassociated from the protease, hence the term. Also see Figure 20 in Supplementary Material.

4 Two otherwise identical systems are said to be in different crowder configurations if their crowders are placed at different locations.

5 apo-m10 was not studied as the original objectives were to study drug-receptor interactions in various physiological environments.