{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:55:02Z","timestamp":1789844102284,"version":"4.0.1"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Autosomal recessive Parkinson\u2019s disease (ARPD) arises from impaired mitophagy due to dysfunction of the PINK1\/Parkin pathway, where PINK1-mediated phosphorylation of ubiquitin at Ser65 is essential for pathway activation. However, experimental limitations obscure the effects of disease-associated mutations on intrinsically disordered regions (IDRs) and post-translational modification (PTM) dynamics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>An integrated computational pipeline was employed to screen 825 PINK1 missense variants, identifying two high-confidence deleterious mutations, T313M and L347P, within the kinase domain. Variant prioritization was complemented by conserved residue, IDR, and PTM analyses, followed by protein\u2013protein docking, molecular dynamics simulations, MM\/PBSA binding free-energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      T313M overlapped a conserved phosphorylation site, whereas L347P mapped to conserved active-site residues, with complementary support from IDR analysis. Docking analysis revealed a progressive reduction in binding affinity from the wild type (\u201388.4 \u00b1 8.2) to L347P (\u201381.9 \u00b1 3.4) and T313M (\u201377.4 \u00b1 4.9), accompanied by decreased electrostatic stabilization (\u2013357.6 \u2192 \u2013260.6 \u2192 \u2013235.5 kcal\/mol) and buried surface area (1741.6 \u2192 1624.1 \u2192 1547.4 \u00c5\n                      <jats:sup>2<\/jats:sup>\n                      ). Molecular dynamics simulations demonstrated that T313M produced the greatest structural and dynamic perturbations, whereas L347P induced moderate destabilization with increased solvent exposure. Although MM\/PBSA analysis indicated broadly comparable binding energetics across all systems, PCA and DCCM analyses revealed increased conformational flexibility and altered residue communication in the mutant complexes, particularly T313M.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings establish a mechanistic link between mutation-induced structural dynamics and impaired PINK1\u2013ubiquitin recognition at Ser65, providing a mutation-specific framework for understanding early mitophagy impairment in ARPD and supporting future molecular assessment and targeted therapeutic development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnmol.2026.1875988","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:39:00Z","timestamp":1785476340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Dynamic structural profiling of PINK1 mutations (T313M and L347P) reveals a vital molecular perturbation namely phospho-Serine 65 ubiquitin recognition point in mitophagy mediated autosomal recessive Parkinson\u2019s disease (ARPD)"],"prefix":"10.3389","volume":"19","author":[{"given":"Deborah","family":"Vincent","sequence":"first","affiliation":[{"name":"Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore","place":["Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Sudandiradoss","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, School of Bio Sciences and Technology, Vellore Institute of Technology, Vellore","place":["Tamil Nadu, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7.20.1","DOI":"10.1002\/0471142905.hg0720s76","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2.","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. 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