Department of Chemistry, University of Delhi, Delhi 110007, India.
J Chem Inf Model. 2021 Apr 26;61(4):1850-1858. doi: 10.1021/acs.jcim.1c00034. Epub 2021 Mar 22.
The hydration thermodynamics of different mutants of α-synuclein (α-syn) related to familial Parkinson's disease (PD) is explored using a computational approach that combines both molecular dynamics simulations in water and integral equation theory of molecular liquids. This analysis focuses on the change in conformational entropy, hydration free energy (HFE), and partial molar volume of α-syn upon mutation. The results show that A53T, A30P, E46K, and H50Q mutants aggregate more readily and display increased HFE and less negative interaction volume than the wild-type α-syn. In contrast, an opposite trend is observed for the G51D mutant with a lower experimental aggregation rate. The residuewise decomposition analysis of the HFE highlights that the dehydration/hydration of the hydrophilic residue-rich N- and C-termini of α-syn majorly contributes to the change upon mutation. The hydration shell contributions of different residues to the interaction volume are consistent with its increase/decrease upon mutation. This work shows that both HFE and interaction volume determine the aggregation kinetics of α-syn upon mutation and may serve as an appropriate benchmark for the treatment of PD.
使用一种结合了分子动力学模拟和分子液体积分方程理论的计算方法，探索了与家族性帕金森病（PD）相关的不同α-突触核蛋白（α-syn）突变体的水合热力学。该分析侧重于突变后α-syn 的构象熵、水合自由能（HFE）和偏摩尔体积的变化。结果表明，A53T、A30P、E46K 和 H50Q 突变体更容易聚集，并且与野生型 α-syn 相比，HFE 增加，相互作用体积的负值减小。相比之下，实验聚集速率较低的 G51D 突变体则呈现出相反的趋势。HFE 的残基分解分析表明，α-syn 的亲水残基丰富的 N-和 C-末端的去水/水合主要导致突变后的变化。不同残基对相互作用体积的水合壳贡献与其突变后的增加/减少一致。这项工作表明，HFE 和相互作用体积都决定了突变后α-syn 的聚集动力学，可能成为治疗 PD 的合适基准。
