Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by the formation of extracellular amyloid‐β (Aβ) plaques. The underlying cause of AD is unknown, however, post‐translational modifications (PTMs) of Aβ have been found in AD patients and are thought to play a role in protein aggregation. One such PTM is pyroglutamylation, which can occur at two sites in Aβ, Glu3 and Glu11. This modification of Aβ involves the truncation and charge‐neutralization of N‐terminal glutamate, causing Aβ to become more hydrophobic and prone to aggregation. The molecular mechanism by which the introduction of pyroglutamate (pE) promotes aggregation has not been determined. To gain a greater understanding of the role that charge neutralization and truncation of the N‐terminus plays on Aβ conformational sampling, we used the Drude polarizable force field (FF) to perform molecular dynamics simulations on AβpE3–42 and AβpE11–42 and comparing their properties to previous simulations of Aβ1–42. The Drude polarizable FF allows for a more accurate representation of electrostatic interactions, therefore providing novel insights into the role that charge plays in protein dynamics. Here, we report the parametrization of pE in the Drude polarizable FF and the effect of pyroglutamylation on Aβ. We found that AβpE3–42 and AβpE11–42 alter the permanent and induced dipoles of the peptide. Specifically, we found that AβpE3–42 and AβpE11–42 have modification‐specific backbone and sidechain polarization response and perturbed solvation properties that shift the Aβ conformational ensemble.

中文翻译：

---

焦谷氨酰化调节淀粉样β-肽的电子特性和构象整体

阿尔茨海默病 (AD) 是一种神经退行性疾病，其特征是细胞外淀粉样蛋白-β (Aβ) 斑块的形成。AD 的根本原因尚不清楚，但在 AD 患者中发现了 Aβ 的翻译后修饰 (PTM)，并且被认为在蛋白质聚集中发挥作用。其中一种 PTM 是焦谷氨酰化，它可以发生在 Aβ、Glu3 和 Glu11 的两个位点。Aβ 的这种修饰涉及 N 末端谷氨酸的截断和电荷中和，导致 Aβ 变得更加疏水并易于聚集。引入焦谷氨酸（pE）促进聚集的分子机制尚未确定。为了更好地了解电荷中和和 N 端截断对 Aβ 构象采样的作用，我们使用 Drude 极化力场 (FF) 对 Aβ 进行分子动力学模拟pE3–42和 AβpE11–42并将它们的特性与之前的 Aβ 模拟进行比较1–42。Drude 可极化 FF 可以更准确地表示静电相互作用，从而为电荷在蛋白质动力学中的作用提供新的见解。在这里，我们报告了 Drude 可极化 FF 中 pE 的参数化以及焦谷氨酰化对 Aβ 的影响。我们发现AβpE3–42和 AβpE11–42改变肽的永久偶极子和诱导偶极子。具体来说，我们发现 AβpE3–42和 AβpE11–42具有修饰特异性的主链和侧链极化响应以及扰动的溶剂化特性，从而改变 Aβ 构象整体。