Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR(CSIC), Universidad de Zaragoza, Zaragoza 50018, Spain.
Biocomputation and Complex Systems Physics Institute (BIFI)-Joint Unit BIFI-IQFR(CSIC), Universidad de Zaragoza, Zaragoza 50018, Spain.
Biophys Chem. 2021 Feb;269:106520. doi: 10.1016/j.bpc.2020.106520. Epub 2020 Dec 5.
The understanding of the complex conformational landscape of amyloid aggregation and its modulation by relevant physicochemical and cellular factors is a prerequisite for elucidating some of the molecular basis of pathology in amyloid related diseases, and for developing and evaluating effective disease-specific therapeutics to reduce or eliminate the underlying sources of toxicity in these diseases. Interactions of proteins with solvating water have been long considered to be fundamental in mediating their function and folding; however, the relevance of water in the process of protein amyloid aggregation has been largely overlooked. Here, we provide a perspective on the role water plays in triggering primary amyloid nucleation of intrinsically disordered proteins (IDPs) based on recent experimental evidences. The initiation of amyloid aggregation likely results from the synergistic effect between both protein intermolecular interactions and the properties of the water hydration layer of the protein surface. While the self-assembly of both hydrophobic and hydrophilic IDPs would be thermodynamically favoured due to large water entropy contributions, large desolvation energy barriers are expected, particularly for the nucleation of hydrophilic IDPs. Under highly hydrating conditions, primary nucleation is slow, being facilitated by the presence of nucleation-active surfaces (heterogeneous nucleation). Under conditions of poor water activity, such as those found in the interior of protein droplets generated by liquid-liquid phase separation, however, the desolvation energy barrier is significantly reduced, and nucleation can occur very rapidly in the bulk of the solution (homogeneous nucleation), giving rise to structurally distinct amyloid polymorphs. Water, therefore, plays a key role in modulating the transition free energy of amyloid nucleation, thus governing the initiation of the process, and dictating the type of preferred primary nucleation and the type of amyloid polymorph generated, which could vary depending on the particular microenvironment that the protein molecules encounter in the cell.
理解淀粉样蛋白聚集的复杂构象景观及其受相关物理化学和细胞因素的调节，是阐明淀粉样蛋白相关疾病中一些分子基础的前提，并开发和评估有效的针对疾病的治疗方法，以减少或消除这些疾病中潜在的毒性来源。长期以来，人们一直认为蛋白质与溶剂水的相互作用对于调节其功能和折叠至关重要；然而，蛋白质在淀粉样蛋白聚集过程中，水的相关性在很大程度上被忽视了。本文基于最近的实验证据，提供了一种观点，即水在触发无规卷曲蛋白质（IDP）的初级淀粉样核形成中所起的作用。淀粉样蛋白聚集的起始可能是由于蛋白质分子间相互作用和蛋白质表面水合层的性质之间的协同作用所致。虽然由于大的水熵贡献，疏水性和亲水性 IDP 的自组装在热力学上是有利的，但预计会有大的去溶剂化能垒，特别是对于亲水性 IDP 的核形成。在高度水合的条件下，由于存在成核活性表面（异质成核），初级成核缓慢，有利于成核。然而，在水活度差的条件下，例如在液-液相分离产生的蛋白质液滴内部发现的条件下，去溶剂化能垒显著降低，核可以在溶液的本体中迅速发生（均相成核），从而产生结构上不同的淀粉样蛋白多晶型物。因此，水在调节淀粉样蛋白核形成的自由能转变中起着关键作用，从而控制着起始过程，并决定了首选的初级成核的类型和产生的淀粉样蛋白多晶型物的类型，这可能取决于蛋白质分子在细胞中遇到的特定微环境。
