Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada.
Proteins. 2011 Jan;79(1):1-22. doi: 10.1002/prot.22854. Epub 2010 Oct 11.
The capacity to form β-sheet structure and to self-organize into amyloid aggregates is a property shared by many proteins. Severe neurodegenerative pathologies such as Alzheimer's disease are thought to involve the interaction of amyloidogenic protein oligomers with neuronal membranes. To understand the experimentally observed catalysis of amyloid formation by lipid membranes and other water-hydrophobic interfaces, we examine the physico-chemical basis of peptide adsorption and aggregation in a model membrane using atomistic molecular simulations. Blocked octapeptides with simple, repetitive sequences, (Gly-Ala)₄, and (Gly-Val)₄, are used as models of β-sheet-forming polypeptide chains found in the core of amyloid fibrils. In the presence of an n-octane phase mimicking the core of lipid membranes, the peptides spontaneously partition at the octane-water interface. The adsorption of nonpolar sidechains displaces the peptides' conformational equilibrium from a heterogeneous ensemble characterized by a high degree of structural disorder toward a more ordered ensemble favoring β-hairpins and elongated β-strands. At the interface, peptides spontaneously aggregate and rapidly evolve β-sheet structure on a 10 to 100 ns time scale, while aqueous aggregates remain amorphous. Catalysis of β-sheet formation results from the combination of the hydrophobic effect and of reduced conformational entropy of the polypeptide chain. While the former drives interfacial partition and displaces the conformational equilibrium of monomeric peptides, the planar interface further facilitates β-sheet organization by increasing peptide concentration and reducing the dimensionality of self-assembly from three to two. These findings suggest a general mechanism for the formation of β-sheets on the surface of globular proteins and for amyloid self-organization at hydrophobic interfaces.
β-折叠结构的形成能力和自组织成淀粉样纤维的能力是许多蛋白质共有的特性。严重的神经退行性疾病，如阿尔茨海默病，被认为涉及淀粉样蛋白寡聚物与神经元膜的相互作用。为了理解脂质膜和其他水-疏水环境中观察到的淀粉样形成的实验催化作用，我们使用原子分子模拟研究了模型膜中肽吸附和聚集的物理化学基础。具有简单重复序列的封闭八肽（Gly-Ala）₄和（Gly-Val）₄被用作在淀粉样纤维核心中发现的β-折叠多肽链的模型。在模拟脂质膜核心的正辛烷相中，肽在辛烷-水界面自发分配。非极性侧链的吸附将肽的构象平衡从具有高度结构无序的不均匀系综转移到有利于β发夹和伸长β-链的更有序系综。在界面上，肽自发聚集并在 10 到 100ns 的时间尺度上迅速演化出β-折叠结构，而水相聚集物仍保持无定形。β-折叠形成的催化作用是疏水效应和多肽链构象熵降低的结合。前者驱动界面分配并取代单体肽的构象平衡，而平面界面通过增加肽浓度和降低自组装的维度（从三维到二维）进一步促进β-折叠组织。这些发现为球状蛋白表面β-折叠的形成和疏水界面上淀粉样自组织提供了一种普遍机制。
