Liu Ju, Wang Yanlei, Huo Feng, He Hongyan
Beijing Key Laboratory of Ionic Liquids Clean Process, State Key Laboratory of Mesoscience and Engineering, CAS Key Laboratory of Green Process and Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
Fundam Res. 2024 Feb 7;4(4):777-784. doi: 10.1016/j.fmre.2023.12.013. eCollection 2024 Jul.
Abnormalities in the transition between α-helices and β-sheets (α-β transition) may lead to devastating neurodegenerative diseases, such as Parkinson's syndrome and Alzheimer's disease. Ionic liquids (ILs) are potential drugs for targeted therapies against these diseases because of their excellent bioactivity and designability of ILs. However, the mechanism through which ILs regulate the α-β transition remains unclear. Herein, a combination of GPU-accelerated microsecond molecular dynamics simulations, correlation analysis, and machine learning was used to probe the dynamical α-β transition process induced by ILs of 1-alkyl-3-methylimidazolium chloride ([C mim]Cl) and its molecular mechanism. Interestingly, the cation of [C mim] in ILs can spontaneously insert into the peptides as free ions ( ≤ 10) and clusters ( ≥ 11). Such insertion can significantly inhibit the α-β, transition and the inhibiting ability for the clusters is more significant than that of free ions, where [Cmim] and [Cmim] can reduce the maximum β-sheet content of the peptide by 18.5% and 44.9%, respectively. Furthermore, the correlation analysis and machine learning method were used to develop a predictive model accounting for the influencing factors on the α-β transition, which could accurately predict the effect of ILs on the α-β transition. Overall, these quantitative results may not only deepen the understanding of the role of ILs in the α-β transition but also guide the development of the IL-based treatments for related diseases.
α-螺旋与β-折叠之间转变（α-β转变）异常可能导致毁灭性的神经退行性疾病，如帕金森综合征和阿尔茨海默病。离子液体（ILs）因其出色的生物活性和可设计性而成为针对这些疾病的靶向治疗潜在药物。然而，ILs调节α-β转变的机制仍不清楚。在此，结合GPU加速的微秒级分子动力学模拟、相关分析和机器学习，探究了1-烷基-3-甲基咪唑鎓氯化物（[C mim]Cl）离子液体诱导的动态α-β转变过程及其分子机制。有趣的是，离子液体中[C mim]的阳离子可以作为游离离子（≤10）和簇（≥11）自发插入肽中。这种插入可显著抑制α-β转变，且簇的抑制能力比游离离子更强，其中[Cmim]和[Cmim]可分别将肽的最大β-折叠含量降低18.5%和44.9%。此外，利用相关分析和机器学习方法建立了一个预测模型，该模型考虑了影响α-β转变的因素，能够准确预测离子液体对α-β转变的影响。总体而言，这些定量结果不仅可能加深对离子液体在α-β转变中作用的理解，还可能指导基于离子液体的相关疾病治疗方法的开发。
