{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T06:22:24Z","timestamp":1771568544976,"version":"3.50.1"},"reference-count":81,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010728","name":"ICAR-Indian Veterinary Research Institute","doi-asserted-by":"publisher","award":["No.F.7-40\/Biochem.\/2022-23\/JD(R)"],"award-info":[{"award-number":["No.F.7-40\/Biochem.\/2022-23\/JD(R)"]}],"id":[{"id":"10.13039\/501100010728","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Alpha-synucleinopathies, characterized by extracellular alpha-synuclein (\u03b1Syn or SNCA) accumulation and aggregation, have been linked to neurological disorders including Parkinson\u2019s disease and multiple system atrophy. P2RX7 is a non-selective cationic transmembrane purinergic receptor activated by elevated levels of extracellular ATP, which typically occurs during inflammatory conditions. Activation of P2RX7 by \u03b1Syn is implicated in neuronal degeneration, potentially causing pore dilation and increased inflammation. By integrating the data curation, molecular docking, and molecular dynamics (MD) simulations, along with structural analyses, we attempted to elucidate the molecular mechanisms and binding sites for P2RX7-\u03b1Syn interaction. We elucidated interactions between P2RX7 and the N-terminal domain (NTD) of \u03b1Syn. Utilizing cryo-EM structures of P2RX7 in ATP-bound and unbound states, we assessed \u03b1Syn\u2019s effect on P2RX7 structural and functional dynamics. Initially, the analyses revealed that \u03b1Syn interactomes are mainly involved in mitochondrial functions, while P2RX7 interactors are linked to receptor internalization and calcium transport. Molecular docking with six tools identified that \u03b1Syn-NTD fragments preferentially bind to the proximal region of P2RX7\u2019s transmembrane domain. Microsecond all atom MD simulations in a POPS lipid bilayer showed significant atomic fluctuations, particularly in the head region, lower body, and large loop of P2RX7\u2019s cytoplasmic domain. Secondary structure analysis indicated unfolding in regions related to pore dilation and receptor desensitization. Further by contact-based and solvent accessibility analyses, along with protein structure network (PSN) studies, we identified crucial residues involved in \u03b1Syn-P2RX7 interactions. This understanding enhances the knowledge of how \u03b1Syn and P2RX7 interactions take place, potentially contributing to neurodegenerative diseases, and could be instrumental in developing future preventive and therapeutic approaches.<\/jats:p>","DOI":"10.1371\/journal.pone.0319098","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T17:33:08Z","timestamp":1746207188000},"page":"e0319098","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mechanistic insights into Alpha-Synuclein binding to P2RX7: A molecular dynamic and docking 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