ORIGINAL RESEARCH article
Front. Phys.
Sec. Biophysics
Volume 13 - 2025 | doi: 10.3389/fphy.2025.1591640
This article is part of the Research TopicAdvancing Understanding of Biological and Nanostructured Materials Through Atomistic SimulationsView all 5 articles
Oxidation-Induced Destabilization of Polymorphic α-Synuclein Fibrils: Insights from Molecular Dynamics
Provisionally accepted
Tohir Akramov1*
Parthiban Marimuthu2
Mukhriddin Makhkamov1
Aamir Shahzad3
Rasulbek Mashalov1
Jamoliddin Razzokov4*- 1Centre for Advanced Technologies, University 7, 100174 Tashkent, Uzbekistan, Tashkent, Uzbekistan
- 2Åbo Akademi University, Turku, Finland
- 3Government College University, Faisalabad, Faisalabad, Punjab, Pakistan
- 4Tashkent Institute of Irrigation and Agricultural Mechanization Engineers (TIIAME), Tashkent, Uzbekistan
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The build-up of α-Synuclein (αSyn) fibrils is a key feature of Parkinson's disease (PD) and other synucleinopathies. While oxidative stress has been implicated in αSyn aggregation, its precise effects on fibril stability remain unclear. In this study, we use molecular dynamics (MD) simulations and enhanced sampling techniques to investigate the impact of oxidation-induced modifications on the conformational stability of αSyn polymorph fibrils. Three oxidation models (OX1, OX2, and OX3), featuring progressively increased oxidation levels, were generated and compared to the native fibril structure. Key structural analyses, including root mean square deviation (RMSD), secondary structure content, solvent-accessible surface area (SASA), and hydrogen bonding, reveal that oxidation induces significant destabilization of αSyn polymorph fibrils. Free Energy Landscape (FEL) analysis highlights a shift toward more flexible and less compact conformations upon oxidation. Additionally, potential of mean force (PMF) calculations indicate that oxidation weakens inter-chain interactions, lowering the dissociation free energy and suggesting an increased propensity for fibril disassembly. Notably, oxidation disrupts key salt bridges (Glu46-Lys80, Lys45-Glu57) and the hydrophobic packing of Phe94, further contributing to structural destabilization. These findings provide molecular insights into how oxidative modifications influence αSyn polymorph fibril dynamics, reinforcing the role of oxidative stress in fibril destabilization. A more in-depth understanding of these mechanisms could inform therapeutic strategies aimed at preventing or reversing αSyn complex aggregates in neurodegenerative diseases.
Keywords: PD, Parkinson's desease, CAP, Cold atmospheric plasma, Alpha-synucein, Oxidation, Molecular dynamcis, Umbrella sampling (US)
Received: 14 Mar 2025; Accepted: 05 Jun 2025.
Copyright: © 2025 Akramov, Marimuthu, Makhkamov, Shahzad, Mashalov and Razzokov. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Tohir Akramov, Centre for Advanced Technologies, University 7, 100174 Tashkent, Uzbekistan, Tashkent, Uzbekistan
Jamoliddin Razzokov, Tashkent Institute of Irrigation and Agricultural Mechanization Engineers (TIIAME), Tashkent, Uzbekistan
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