α-Synuclein (α-syn) is an abundant presynaptic neuronal protein whose aggregation is strongly associated with Parkinson’s disease. It has been proposed that lipid membranes significantly affect α-syn’s aggregation process. Extensive studies have been conducted to understand the interactions between α-syn and lipid membranes and have demonstrated that the N-terminus plays a critical role. However, the dynamics of the interactions and the conformational transitions of the N-terminus of α-syn at the atomistic scale details are still highly desired. In this study, we performed extensive enhanced sampling molecular dynamics simulations to quantify the folding and interactions of wild-type and N-terminally acetylated α-syn when interacting with lipid structures. We found that N-terminal acetylation significantly increases the helicity of the first few residues in solution or when interacting with lipid membranes. The observations in simulations showed that the binding of α-syn with lipid membranes mainly follows the induced-fit model, where the disordered α-syn binds with the lipid membrane through the electrostatic interactions and hydrophobic contacts with the packing defects; after stable insertion, N-terminal acetylation promotes the helical folding of the N-terminus to enhance the anchoring, thus increasing the binding affinity. We have shown the critical role of the first N-terminal residue methionine for recognition and anchoring to the negatively charged membrane. Although N-terminal acetylation neutralizes the positive charge of Met1 that may affect the electrostatic interactions of α-syn with membranes, the increase in helicity of the N-terminus should compensate for the binding affinity. This study provides detailed insight into the folding dynamics of α-syn’s N-terminus with or without acetylation in solution and upon interaction with lipids, which clarifies how the N-terminal acetylation regulates the affinity of α-syn binding to lipid membranes. It also shows how packing defects and electrostatic effects coregulate the N-terminus of α-syn folding and its interaction with membranes.

中文翻译：

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N 末端乙酰化 α-突触核蛋白与脂质膜相互作用时的折叠


α-突触核蛋白 （α-syn） 是一种丰富的突触前神经元蛋白，其聚集与帕金森病密切相关。有人提出脂质膜显着影响 α-syn 的聚集过程。已经进行了广泛的研究以了解 α-syn 和脂质膜之间的相互作用，并证明 N 端起着关键作用。然而，在原子尺度细节上，α-syn 的相互作用动力学和 N 端的构象转变仍然非常需要。在这项研究中，我们进行了广泛的增强采样分子动力学模拟，以量化野生型和 N 末端乙酰化 α-syn 在与脂质结构相互作用时的折叠和相互作用。我们发现 N 末端乙酰化显着增加了溶液中或与脂质膜相互作用时前几个残基的螺旋度。模拟中的观察结果表明，α-syn 与脂质膜的结合主要遵循诱导拟合模型，其中无序的 α-syn 通过与堆积缺陷的静电相互作用和疏水接触与脂质膜结合;稳定插入后，N 端乙酰化促进 N 端的螺旋折叠以增强锚定，从而增加结合亲和力。我们已经证明了第一个 N 末端残基蛋氨酸对于识别和锚定到带负电荷的膜上的关键作用。尽管 N 端乙酰化中和了 Met1 的正电荷，这可能会影响 α-syn 与膜的静电相互作用，但 N 端螺旋度的增加应该补偿结合亲和力。 本研究详细介绍了 α-syn 的 N 端在溶液中以及与脂质相互作用时有或没有乙酰化的折叠动力学，这阐明了 N 端乙酰化如何调节 α-syn 结合与脂质膜的亲和力。它还显示了堆积缺陷和静电效应如何共同调节 α-syn 折叠的 N 端及其与膜的相互作用。