SARS‐CoV‐2 Mpro Dihedral Angles Reveal Allosteric Signaling

• Published in: Proteins, structure, function, and bioinformatics Vol. 93; no. 7; pp. 1281 - 1289
• Main Authors: Evans, Daniel, Sheraz, Samreen, Lau, Albert Y.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.07.2025; Wiley Subscription Services, Inc
• Subjects: Allosteric properties; Allosteric Regulation; Allosteric Site; Binding Sites; Catalytic Domain; computational chemistry; coronavirus 3C proteases; Coronavirus 3C Proteases - chemistry; Coronavirus 3C Proteases - metabolism; Humans; Models, Molecular; Molecular Dynamics Simulation; Protein Binding; Protein Conformation; Proteins; SARS-CoV-2 - chemistry; SARS-CoV-2 - enzymology; SARS‐CoV‐2; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Signal Transduction; Therapeutic targets; protein conformation; computational chemistry; SARS‐CoV‐2; coronavirus 3C proteases; molecular dynamics simulation
• ISSN: 0887-3585; 1097-0134; 1097-0134
• DOI: 10.1002/prot.26814

ABSTRACT In allosteric proteins, identifying the pathways that signals take from allosteric ligand‐binding sites to enzyme active sites or binding pockets and interfaces remains challenging. This avenue of research is motivated by the goals of understanding particular macromolecular systems of interest and creating general methods for their study. An especially important protein that is the subject of many investigations in allostery is the SARS‐CoV‐2 main protease (Mpro), which is necessary for coronaviral replication. It is both an attractive drug target and, due to intense interest in it for the development of pharmaceutical compounds, a gauge of the state of the art approaches in studying protein inhibition. Here we develop a computational method for characterizing protein allostery and use it to study Mpro. We propose a role of the protein's C‐terminal tail in allosteric modulation and warn of unintuitive traps that can plague studies of the role of protein dihedral angles in transmitting allosteric signals.