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The highly conserved homo\u2010dimeric chymotrypsin\u2010like protease (3CL M<jats:sup>PRO<\/jats:sup>), belonging to the class of cysteine hydrolases, plays an indispensable role in processing viral polyproteins that are involved in viral replication and transcription. Studies have successfully demonstrated the role of M<jats:sup>PRO<\/jats:sup> as an attractive drug target for designing antiviral treatments because of its importance in the viral life cycle. Herein, we report the structural dynamics of six experimentally solved structures of M<jats:sup>PRO<\/jats:sup> (i.e.,\u00a06LU7, 6M03, 6WQF, 6Y2E, 6Y84, and 7BUY including both ligand\u2010free and ligand\u2010bound states) at different resolutions. We have employed a structure\u2010based balanced forcefield, CHARMM36m through state\u2010of\u2010the\u2010art all\u2010atoms molecular dynamics simulations at \u00b5\u2010seconds scale at room temperature\u00a0(303K) and pH 7.0 to explore their structure\u2010function relationship. The helical domain\u2010III responsible for dimerization mostly contributes to the altered conformational states and destabilization of M<jats:sup>PRO<\/jats:sup>. A keen observation of the high degree of flexibility in the P5 binding pocket adjoining domain II\u2010III highlights the reason for observation of conformational heterogeneity among the structural ensembles of M<jats:sup>PRO<\/jats:sup>. We also observe a differential dynamics of the catalytic pocket residues His41, Cys145, and Asp187, which may lead to catalytic impairment of the monomeric proteases. Among the highly populated conformational states of the six systems, 6LU7 and 7M03 forms the most stable and compact M<jats:sup>PRO<\/jats:sup> conformation with intact catalytic site and structural integrity. Altogether, our findings from this extensive study provides a benchmark to identify physiologically relevant structures of such promising drug targets for structure\u2010based drug design and discovery of potent drug\u2010like compounds having clinical potential.<\/jats:p>","DOI":"10.1002\/jcb.30409","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T18:36:21Z","timestamp":1682534181000},"page":"861-876","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Structural insights into SARS\u2010CoV\u20102 main protease conformational plasticity"],"prefix":"10.1002","volume":"124","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-8454","authenticated-orcid":false,"given":"Budheswar","family":"Dehury","sequence":"first","affiliation":[{"name":"Division of Bioinformatics ICMR\u2010Regional Medical Research Centre  Bhubaneswar Odisha 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