Pacific Quantum Center, Far Eastern Federal University, 690922, Vladivostok, Russia.
Baker Laboratory of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853-1301, United States.
J Phys Chem B. 2022 Sep 15;126(36):6878-6890. doi: 10.1021/acs.jpcb.2c04651. Epub 2022 Sep 2.
α-Synuclein (αS) is the principal protein component of the Lewy body and Lewy neurite deposits that are found in the brains of the victims of one of the most prevalent neurodegenerative disorders, Parkinson's disease. αS can be qualified as a chameleon protein because of the large number of different conformations that it is able to adopt: it is disordered under physiological conditions in solution, in equilibrium with a minor α-helical tetrameric form in the cytoplasm, and is α-helical when bound to a cell membrane. Also, , αS forms polymorphic amyloid fibrils with unique arrangements of cross-β-sheet motifs. Therefore, it is of interest to elucidate the origins of the structural flexibility of αS and what makes αS stable in different conformations. We address these questions here by analyzing the experimental structures of the micelle-bound, tetrameric, and fibrillar αS in terms of a kink (heteroclinic standing wave solution) of a generalized discrete nonlinear Schrödinger equation. It is illustrated that without molecular dynamics simulations the kinks are capable of identifying the key residues causing structural flexibility of αS. Also, the stability of the experimental structures of αS is investigated by simulating heating/cooling trajectories using the Glauber algorithm. The findings are consistent with experiments.
α-突触核蛋白（αS）是路易体和路易神经突沉积物的主要蛋白质成分，这些沉积物存在于帕金森病等最常见的神经退行性疾病患者的大脑中。由于其能够采用的大量不同构象，αS 可以被定性为变色龙蛋白：在溶液中的生理条件下，它处于无序状态，与细胞质中少量的α-螺旋四聚体形式处于平衡状态，与细胞膜结合时呈α-螺旋。此外，αS 还形成具有独特交叉β-片层结构排列的多态性淀粉样纤维。因此，阐明αS 结构灵活性的起源以及使αS 在不同构象中稳定的原因是很有意义的。我们通过分析胶束结合的、四聚体的和纤维状的 αS 的实验结构，根据广义离散非线性薛定谔方程的扭结（异宿驻波解）来解决这些问题。结果表明，在没有分子动力学模拟的情况下，扭结能够识别导致 αS 结构灵活性的关键残基。此外，还通过使用格劳伯算法模拟加热/冷却轨迹来研究 αS 的实验结构的稳定性。研究结果与实验一致。
