Candidate Binding Sites for Allosteric Inhibition of the SARS-CoV-2 Main Protease from the Analysis of Large-Scale Molecular Dynamics Simulations
| Autor: | Alessandro Laio, Giulia Sormani, Matteo Carli, Alex Rodriguez |
|---|---|
| Přispěvatelé: | Carli, M., Sormani, G., Rodriguez Garcia, A., Laio, A. |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular 0301 basic medicine Letter Protein Conformation medicine.medical_treatment Protease Inhibitor Allosteric regulation Viral Protease Plasma protein binding Molecular Dynamics Simulation 01 natural sciences Settore FIS/03 - Fisica della Materia 03 medical and health sciences Molecular dynamics Protein structure Models 0103 physical sciences medicine Humans Protease Inhibitors General Materials Science Binding site Physical and Theoretical Chemistry Binding Sites Protease 010304 chemical physics SARS-CoV-2 Viral Proteases Chemistry Binding Site Molecular COVID-19 Energy landscape 030104 developmental biology Chemical physics Protein Binding Function (biology) Human Model |
| Zdroj: | The Journal of Physical Chemistry Letters |
| ISSN: | 1948-7185 |
| DOI: | 10.1021/acs.jpclett.0c03182 |
| Popis: | We analyzed a 100 μs 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. |
| Databáze: | OpenAIRE |
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