The aggregation of Aβ42 peptides is considered as one of the main causes for the development of Alzheimer's disease. In this context, Zn²⁺ and Cu²⁺ play a significant role in regulating the aggregation mechanism, due to changes in the structural and the solvation free energy of Aβ42. In practice, experimental studies are not able to determine the latter properties, since the Aβ42–Zn²⁺ and Aβ42–Cu²⁺ peptide complexes are intrinsically disordered, exhibiting rapid conformational changes in the aqueous environment. Here, we investigate atomic structural variations and the solvation thermodynamics of Aβ42_, Aβ42–Cu²⁺, and Aβ42–Zn²⁺ systems in explicit solvent (water) by using quantum chemical structures as templates for a metal binding site and combining extensive all‐atom molecular dynamics (MD) simulations with a thorough solvation thermodynamic analysis. Our results show that the zinc and copper coordination results in a significant decrease of the solvation free energy in the C‐terminal region (Met35‐Val40), which in turn leads to a higher structural disorder. In contrast, the β‐sheet formation at the same C‐terminal region indicates a higher solvation free energy in the case of Aβ42_. The solvation free energy of Aβ42 increases upon Zn²⁺ binding, due to the higher tendency of forming the β‐sheet structure at the Leu17‐Ala42 residues, in contrast to the case of binding with Cu²⁺. Finally, we find the hydrophobicity of Aβ42–Zn²⁺ in water is greater than in the case of Aβ42–Cu²⁺.

中文翻译：

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锌结合比铜结合促进阿尔茨海默氏症Aβ42肽更大的疏水性：分子动力学和溶剂化热力学研究。

Aβ42肽的聚集被认为是阿尔茨海默氏病发展的主要原因之一。在这种情况下，由于Aβ42的结构和溶剂化自由能的变化，Zn ²⁺和Cu ²⁺在调节聚集机理中起着重要作用。在实践中，由于Aβ42–Zn ²⁺和Aβ42–Cu ²⁺肽复合物本质上是无序的，因此实验研究无法确定后者的性质，在水性环境中表现出快速的构象变化。在这里，我们研究了Aβ42 _， Aβ42–Cu ²⁺和Aβ42–Zn ^2+的原子结构变化和溶剂化热力学。通过使用量子化学结构作为金属结合位点的模板，并将广泛的全原子分子动力学（MD）模拟与彻底的溶剂化热力学分析相结合，在显式溶剂（水）中形成系统。我们的结果表明，锌和铜的配位导致C端区域（Met35-Val40）的溶剂化自由能显着降低，进而导致更高的结构紊乱。相反，在Aβ42的情况下，在相同C端区域形成β-折叠表示较高的溶剂化自由能_。Zn ²⁺结合后，Aβ42的溶剂化自由能增加，这是因为与Cu ²⁺结合的情况相比，在Leu17-Ala42残基形成β-折叠结构的趋势更高。最后，我们发现水中Aβ42–Zn ²⁺的疏水性大于Aβ42–Cu ²⁺的疏水性。