Department of Chemistry, The University of Texas at San Antonio, One UTSA Circle, San Antonio, TX 78249, USA.
ACS Chem Neurosci. 2013 Mar 20;4(3):486-97. doi: 10.1021/cn300198q. Epub 2013 Jan 30.
The genetic missense A30P mutation of the wild-type α-synuclein protein results in the replacement of the 30th amino acid residue from alanine (Ala) to proline (Pro) and was initially found in the members of a German family who developed Parkinson's disease. Even though the structures of these proteins have been measured before, detailed understanding about the structures and their relationships with free energy landscapes is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. We report the secondary and tertiary structures and conformational free energy landscapes of the wild-type and A30P mutant-type α-synuclein proteins in an aqueous solution environment via extensive parallel tempering molecular dynamics simulations along with thermodynamic calculations. In addition, we present the residual secondary structure component transition stabilities at the atomic level with dynamics in terms of free energy change calculations using a new strategy that we reported most recently. Our studies yield new interesting results; for instance, we find that the A30P mutation has local as well as long-range effects on the structural properties of the wild-type α-synuclein protein. The helical content at Ala18-Gly31 is less prominent in comparison to the wild-type α-synuclein protein. The β-sheet structure abundance decreases in the N-terminal region upon A30P mutation of the wild-type α-synuclein, whereas the NAC and C-terminal regions possess larger tendencies for β-sheet structure formation. Long-range intramolecular protein interactions are less abundant upon A30P mutation, especially between the NAC and C-terminal regions, which is linked to the less compact and less stable structures of the A30P mutant-type rather than the wild-type α-synuclein protein. Results including the usage of our new strategy for secondary structure transition stabilities show that the A30P mutant-type α-synuclein tendency toward aggregation is higher than the wild-type α-synuclein but we also find that the C-terminal and NAC regions of the A30P mutant-type α-synuclein are reactive toward fibrillzation and aggregation based on atomic level studies with dynamics in an aqueous solution environment. Therefore, we propose that small molecules or drugs blocking the specific residues, which we report herein, located in the NAC- and C-terminal regions of the A30P mutant-type α-synuclein protein might help to reduce the toxicity of the A30P mutant-type α-synuclein protein.
野生型α-突触核蛋白的遗传错义 A30P 突变导致第 30 个氨基酸残基从丙氨酸（Ala）替换为脯氨酸（Pro），最初在患有帕金森病的德国家族成员中发现。尽管这些蛋白质的结构已经被测量过，但关于它们的结构及其与自由能景观的关系的详细了解还很缺乏，这有助于深入了解帕金森病的发病机制。我们通过广泛的并行温度分子动力学模拟以及热力学计算，报告了在水溶液环境中野生型和 A30P 突变型α-突触核蛋白的二级和三级结构以及构象自由能景观。此外，我们还使用我们最近报道的新策略，以原子水平的残基二级结构成分转变稳定性为研究对象，通过自由能变化计算来呈现动力学变化。我们的研究得出了一些有趣的新结果；例如，我们发现 A30P 突变对野生型α-突触核蛋白的结构特性既有局部影响，也有远程影响。与野生型α-突触核蛋白相比，Ala18-Gly31 处的螺旋含量不那么明显。野生型α-突触核蛋白的 A30P 突变使 N 端区域的β-折叠结构丰度降低，而 NAC 和 C 端区域具有更大的β-折叠结构形成倾向。A30P 突变后，长程分子内相互作用不太丰富，特别是在 NAC 和 C 端区域之间，这与 A30P 突变型而不是野生型α-突触核蛋白的结构不太紧凑和不太稳定有关。包括使用我们的新策略进行二级结构转变稳定性的结果表明，A30P 突变型α-突触核蛋白的聚集趋势高于野生型α-突触核蛋白，但我们也发现 A30P 突变型α-突触核蛋白的 C 端和 NAC 区域在水溶液环境中具有动态的原子水平研究表明，它们对纤维化和聚集具有反应性。因此，我们提出，针对位于 A30P 突变型α-突触核蛋白 NAC 和 C 端的特定残基的小分子或药物，可能有助于减少 A30P 突变型α-突触核蛋白的毒性。
