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DYRK1A, in particular, stands at the center of attention due to its pivotal role. Disruptions in its activity, whether through upregulation or downregulation, have profound implications, notably in neurological disorders and cancer progression. Understanding the impact of phosphorylation, a fundamental post\u2010translational modification, on DYRK1A is paramount. In this study, we delved into the complex interplay of phosphorylation and the effects of the abemaciclib inhibitor on DYRK1A conformational dynamics. We employed advanced techniques such as molecular dynamics simulations and the molecular mechanics Poisson\u2010Boltzmann surface area (MM\/PBSA) scheme and deciphered the intricate dance of DYRK1A's structural elements during phosphorylation. Our exploration revealed intriguing details: the <jats:italic>\u03b1<\/jats:italic>C\u2010helix undergoing outward movement, a distorted <jats:italic>\u03b1<\/jats:italic>C\u2010helix, a wide\u2010open P\u2010loop, extended A\u2010loop, and role of electrostatic interactions shaping A\u2010loop dynamics. Notably, the interaction of specific residues, particularly Lys<jats:sup>188<\/jats:sup>, forming robust salt bridges with Asp<jats:sup>307<\/jats:sup> and Glu<jats:sup>203<\/jats:sup>, plays a pivotal role in shaping the structure of the protein. Diving deeper, we conducted principal component analysis and conformational free energy sampling to uncover crucial structural intermediates. Moreover, our dynamic cross\u2010correlation map sheds light on the influence of phosphorylation by enhancing coordinated movements while dampening anti\u2010correlated motions across various domains. This nuanced understanding of DYRK1A kinase activation, driven by phosphorylation, not only enriches our knowledge but also holds promise in the development of targeted therapies for associated diseases.<\/jats:p>","DOI":"10.1002\/jcc.70172","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T03:20:26Z","timestamp":1751253626000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Unlocking the Conformational Secrets of <scp>DYRK1A<\/scp> Kinase With Computational Microscope: Exploring Phosphorylation\u2010Driven Structural Dynamics"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6861-5912","authenticated-orcid":false,"given":"Kapil Dattatray","family":"Ursal","sequence":"first","affiliation":[{"name":"Department of Biosciences and Biomedical Engineering Indian Institute of Technology Indore  Indore Madhya Pradesh 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