Laboratory of Physical Chemistry, Swiss Federal Institute of Technology, ETH-Hönggerberg, Zürich, Switzerland.
Department of Health Sciences and Technology, Swiss Federal Institute of Technology, IFNH, LFO, Zürich, Switzerland.
Biophys J. 2018 Dec 18;115(12):2336-2347. doi: 10.1016/j.bpj.2018.10.031. Epub 2018 Nov 10.
Interactions between biological membranes and disease-associated amyloids are well documented, and their prevalence suggests that an inherent affinity exists between these molecular assemblies. Our interest in the molecular origins of life have led us to investigate the nature of such interactions in the context of their molecular predecessors (i.e., vesicle-forming amphiphiles and small peptides). Under certain conditions, amyloidogenic peptides or fatty acids are each able to form ordered structures on their own; however, we report here on their cooperative assembly into novel, to our knowledge, highly ordered structures. We first examined an amyloidogenic eight-residue peptide, which forms amyloids at pH 11, yet because of its positive electrostatic character remains soluble at a neutral pH. In mixtures with simple fatty acids, this peptide is also able to form novel, to our knowledge, coaggregates at a neutral pH whose structures are sensitive to both the fatty acid concentration and identity. Below the critical vesicle concentration, the mixtures of fatty acid and peptide yield a flocculent precipitate with an underlying β-structure. Above the critical vesicle concentration, the mixtures yield a translucent precipitate that consists of tube-like structures. Small-angle x-ray scattering and fiber diffraction data were used to model their structures as hollow-core two-shell cylinders in which the inner shell is a bilayer of fatty acid and the outer shell alternates between amyloid and bilayers of fatty acid. The further analysis of decanoic acid with a panel of 13 other basic amyloidogenic peptides confirmed the general nature of the observed interactions. The cooperativity within this heterogeneous system is attributed to the structurally repetitive natures of the fatty acid bilayer and the cross-β-sheet motif, providing compatible scaffolds for attractive electrostatic interactions. We show these interactions to be mutually beneficial, expanding the phase space of both peptides and fatty acids while providing a simple yet robust physical connection between two distinct entities relevant for life.
生物膜与疾病相关淀粉样蛋白之间的相互作用已有充分的文献记载，其普遍性表明这些分子组装体之间存在固有亲和力。我们对生命分子起源的兴趣促使我们在其分子前体（即形成囊泡的两亲性分子和小肽）的背景下研究这些相互作用的性质。在某些条件下，淀粉样蛋白形成肽或脂肪酸本身都能够形成有序结构；然而，我们在这里报告了它们合作组装成新颖的、据我们所知的高度有序结构。我们首先研究了一种淀粉样蛋白形成肽，它在 pH 值为 11 时形成淀粉样蛋白，但由于其正静电特性，在中性 pH 值下仍保持溶解状态。在与简单脂肪酸的混合物中，这种肽也能够形成新颖的、据我们所知的共聚集物，在中性 pH 值下，其结构对脂肪酸浓度和身份都很敏感。在低于临界囊泡浓度下，脂肪酸和肽的混合物产生具有底层β-结构的絮状沉淀。在临界囊泡浓度以上，混合物产生半透明沉淀，由管状结构组成。小角 X 射线散射和纤维衍射数据用于模拟其结构为中空核双层圆柱形，其中内层为脂肪酸双层，外层在淀粉样蛋白和脂肪酸双层之间交替。使用一组 13 种其他碱性淀粉样蛋白对癸酸的进一步分析证实了观察到的相互作用的普遍性。这种异质体系中的协同作用归因于脂肪酸双层和交叉β-片层基序的结构重复性，为有吸引力的静电相互作用提供了兼容的支架。我们表明这些相互作用是互利的，扩大了肽和脂肪酸的相空间，同时为生命中两个不同实体之间提供了简单而稳健的物理联系。
