PINK1 mutasyonlarının (T313M ve L347P) dinamik yapısal profillemesi, mitofaji aracılı otozomal resesif Parkinson hastalığında (ARPD) fosfo-Serine 65 ubiquitin tanıma noktası olarak hayati bir moleküler pertürbasyonu ortaya koymaktadır.

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IntroductionAutosomal recessive Parkinson's 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.MethodsAn 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-protein docking, molecular dynamics simulations, MM/PBSA binding free-energy calculations, principal component analysis (PCA), and dynamic cross-correlation matrix (DCCM) analysis.ResultsT313M 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 (-88.4 ± 8.2) to L347P (-81.9 ± 3.4) and T313M (-77.4 ± 4.9), accompanied by decreased electrostatic stabilization (-357.6 → -260.6 → -235.5 kcal/mol) and buried surface area (1741.6 → 1624.1 → 1547.4 Å2). 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.DiscussionThese findings establish a mechanistic link between mutation-induced structural dynamics and impaired PINK1-ubiquitin recognition at Ser65, providing a mutation-specific framework for understanding early mitophagy impairment in ARPD and supporting future molecular assessment and targeted therapeutic development.

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