Xie Huisi, Guo Cong
Department of Physics and International Centre for Quantum and Molecular Structures, College of Sciences, Shanghai University, Shanghai, China.
Front Mol Biosci. 2021 Feb 23;7:629520. doi: 10.3389/fmolb.2020.629520. eCollection 2020.
Human serum albumin (HSA) is a key endogenous inhibitor of amyloid-β (Αβ) aggregation. In vitro HSA inhibits Aβ fibrillization and targets multiple species along the aggregation pathway including monomers, oligomers, and protofibrils. Amyloid inhibition by HSA has both pathological implications and therapeutic potential, but the underlying molecular mechanism remains elusive. As a first step towards addressing this complex question, we studied the interactions of an Aβ42 monomer with HSA by molecular dynamics simulations. To adequately sample the conformational space, we adapted the replica exchange with solute tempering (REST2) method to selectively heat the Aβ42 peptide in the absence and presence of HSA. Aβ42 binds to multiple sites on HSA with a preference to domain III and adopts various conformations that all differ from the free state. The β-sheet abundances of H14-E22 and A30-M33 regions are significantly reduced by HSA, so are the β-sheet lengths. HSA shifts the conformational ensemble towards more disordered states and alters the β-sheet association patterns. In particular, the frequent association of Q15-V24 and N27-V36 regions into β-hairpin which is critical for aggregation is impeded. HSA primarily interacts with the latter β-region and the N-terminal charged residues. They form promiscuous interactions characterized by salt bridges at the edge of the peptide-protein interface and hydrophobic cores at the center. Consequently, intrapeptide interactions crucial for β-sheet formation are disrupted. Our work builds the bridge between the modification of Aβ conformational ensemble and amyloid inhibition by HSA. It also illustrates the potential of the REST2 method in studying interactions between intrinsically disordered peptides and globular proteins.
人血清白蛋白（HSA）是淀粉样β蛋白（Aβ）聚集的关键内源性抑制剂。在体外，HSA抑制Aβ纤维化，并靶向聚集途径中的多种物质，包括单体、寡聚体和原纤维。HSA对淀粉样蛋白的抑制作用既有病理意义，也有治疗潜力，但其潜在的分子机制仍然难以捉摸。作为解决这个复杂问题的第一步，我们通过分子动力学模拟研究了Aβ42单体与HSA的相互作用。为了充分采样构象空间，我们采用了溶质回火复制交换（REST2）方法，在有无HSA的情况下选择性加热Aβ42肽。Aβ42优先结合到HSA的结构域III上的多个位点，并采用各种与自由状态不同的构象。HSA显著降低了H14-E22和A30-M33区域的β-折叠丰度，β-折叠长度也降低了。HSA将构象集合向更无序的状态转变，并改变了β-折叠的结合模式。特别是，对聚集至关重要的Q15-V24和N27-V36区域频繁形成β-发夹结构的过程受到阻碍。HSA主要与后一个β区域和N端带电荷的残基相互作用。它们形成了混杂的相互作用，其特征是在肽-蛋白质界面边缘有盐桥，在中心有疏水核心。因此，对β-折叠形成至关重要的肽内相互作用被破坏。我们的工作搭建了Aβ构象集合修饰与HSA对淀粉样蛋白抑制作用之间的桥梁。它还说明了REST2方法在研究内在无序肽与球状蛋白之间相互作用方面的潜力。
