b-淀粉样蛋白与人体血清白蛋白相互作用机制的分子模拟研究

Amyloid-beta(Abeta) is an intrinsically disordered protein and its aggregation into fibrils is crucially involved in the etiology of Alzheimer’s disease. Human serum albumin (HSA) is the most abundant protein in both blood plasma and cerebrospinal fluid. HSA can bind Abeta and suppress its aggregation in the human body. Understanding the regulation of Abeta aggregation by HSA is essential for developing novel and safe strategies for curing Alzheimer’s. Evidence indicated that the disordered protein-protein interactions between monomeric Abeta and HSA played an important role. Whereas experimental studies have provided intriguing insights into the structural changes of Abeta upon binding to HSA, disparate behaviors of Abeta40 and Abeta42, and the interference of fatty acids with the Abeta-HSA interactions, molecular details about Abeta-HSA complex on the atomic level are largely unknown. Moreover, the mechanism for the disordered protein-protein interaction is still a mystery. The current project is dedicated to address the questions on Abeta-HSA interaction with extensive molecular dynamics simulations. Here we employ the replica exchange with solute tempering method to adequately sample the conformational space of Abeta with and without HSA by increasing the effective temperature of Abeta only. Firstly, we will characterize the binding sites of Abeta and HSA, the conformational space of the complex, and perturbations to dynamics properties. Based on such a comprehensive molecular picture, we aim to reveal the mechanism for Abeta-HSA interactions, especially the binding-coupled folding of Abeta. Secondly, we will compare the binding behaviors of Abeta40 and Abeta42 and probe the molecular origin of differences induced by two additional C-terminal residues. Last but not least, we will study the effects of fatty acids on the binding sites and conformations of Abeta and HSA and ultimately provide the mechanism by which fatty acids interfere with Abeta binding to HSA. Our research will provide important information for understanding the inhibition of Abeta aggregation by HSA and expand the perspective on disordered protein-protein interactions and their biological implications.

B-淀粉样蛋白（Ab）是天然无序蛋白，其纤维化与阿尔茨海默症紧密相关。人血清白蛋白（HSA）是血浆和脑脊液中含量最高的蛋白，可以抑制Ab纤维化，对研发治疗方法有重要意义。研究表明Ab单体与HSA之间的无序蛋白-蛋白相互作用在抑制纤维化中起到重要作用。虽然实验研究得到了Ab的结构变化、Ab40/42在结合HSA上的性质差异、脂肪酸干预Ab与HSA结合等有趣结果，但Ab-HSA复合体的原子水平细节信息及二者的相互作用机制未知。本项目使用溶质温度副本交换方法实现对构象空间的充分抽样，来解决以上问题。将研究二者的结合位点、结合构象及动力学性质，揭示二者相互作用（尤其是结合-折叠耦合）的机制；对比研究Ab40、Ab42在结合HSA上的性质差异及其原因；研究脂肪酸干预Ab与HSA相互作用的机制。此研究将对HSA抑制Ab纤维化的机制提供深刻见解，拓展对无序蛋白-蛋白相互作用机制及其生物意义的理解。

分子动力学模拟能够提供原子尺度的结构信息及相互作用细节，已发展成为研究蛋白质结构和动力学性质的主要方法之一。蛋白质的结构决定功能，蛋白质的错误折叠形成淀粉样纤维，往往与疾病相关。一个典型的例子是 beta-淀粉样蛋白，由其聚集形成的淀粉样纤维沉淀是阿尔兹海默症的主要病理特征之一，因而被广泛研究。近年研究发现以血清白蛋白为代表的内源性蛋白质可与之发生作用，并调控其聚集过程，但是背后的分子机制并不清楚。本项目使用传统分子动力学及增强抽样方法，模拟了白蛋白与beta-淀粉样蛋白单体、低聚体的结合过程，分析二者的结合动力学、结合位点、结合构象等，系统研究了血清白蛋白抑制beta-淀粉样蛋白聚集的分子机制。本研究发现白蛋白通过多种方式调控beta-淀粉样蛋白的聚集过程，主要结果如下所述：（1）白蛋白可以结合单个或多个beta-淀粉样蛋白分子，二者之间发生典型的非特异性无序蛋白-蛋白相互作用；（2）白蛋白改变beta-淀粉样多肽蛋白的构象空间，降低了与纤维结构类似的构象的概率，从而阻碍纤维状低聚体的形成；（3）白蛋白可以非特异性地结合纤维状的beta-淀粉样蛋白低聚体，倾向于屏蔽纤维末端的疏水beta-片层区域，不利于纤维前体进一步生长为成熟纤维。本研究结果表明白蛋白可以干预beta-淀粉样蛋白聚集的成核和纤维成长阶段，有利于理解内源性蛋白调控淀粉样聚集的分子机制。而且本项目的研究结果突出了无序蛋白-蛋白的非特异性相互作用的重要贡献，在此类生物物理问题中可能具有一定的普适性。

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