Insoluble amyloids rich in cross-β fibrils are observed in a number of neurodegenerative diseases. Depending on the clinicopathology, the amyloids can adopt distinct supramolecular assemblies, termed conformational strains. However, rapid methods to study amyloid in a conformationally specific manner are lacking. We introduce a novel computational method for de novo design of peptides that tile the surface of α-synuclein fibrils in a conformationally specific manner. Our method begins by identifying surfaces that are unique to the conformational strain of interest, which becomes a “target backbone” for the design of a peptide binder. Next, we interrogate structures in the PDB database with high geometric complementarity to the target. Then, we identify secondary structural motifs that interact with this target backbone in a favorable, highly occurring geometry. This method produces monomeric helical motifs with a favorable geometry for interaction with the strands of the underlying amyloid. Each motif is then symmetrically replicated to form a monolayer that tiles the amyloid surface. Finally, amino acid sequences of the peptide binders are computed to provide a sequence with high geometric and physicochemical complementarity to the target amyloid. This method was applied to a conformational strain of α-synuclein fibrils, resulting in a peptide with high specificity for the target relative to other amyloids formed by α-synuclein, tau, or Aβ40. This designed peptide also markedly slowed the formation of α-synuclein amyloids. Overall, this method offers a new tool for examining conformational strains of amyloid proteins.

中文翻译：

---

结合 α-突触核蛋白特定构象的肽的从头设计

在许多神经退行性疾病中观察到富含交叉β原纤维的不溶性淀粉样蛋白。根据临床病理学，淀粉样蛋白可以采用不同的超分子组装体，称为构象菌株。然而，缺乏以构象特异性方式研究淀粉样蛋白的快速方法。我们引入了一种新的计算方法，用于从头设计肽，以构象特异性方式平铺 α-突触核蛋白原纤维的表面。我们的方法首先识别感兴趣的构象应变所特有的表面，该表面成为肽结合剂设计的“目标主链”。接下来，我们询问 PDB 数据库中与目标具有高度几何互补性的结构。然后，我们确定了与该目标主链以有利的、高度出现的几何形状相互作用的二级结构基序。该方法产生具有有利几何形状的单体螺旋基序，以便与下面的淀粉样蛋白链相互作用。然后对称地复制每个图案，形成平铺淀粉样蛋白表面的单层。最后，计算肽结合物的氨基酸序列，以提供与目标淀粉样蛋白具有高度几何和物理化学互补性的序列。该方法应用于 α-突触核蛋白原纤维的构象菌株，相对于由 α-突触核蛋白、tau 或 Aβ40 形成的其他淀粉样蛋白，产生了对靶标具有高特异性的肽。这种设计的肽还显着减缓了 α-突触核蛋白淀粉样蛋白的形成。总体而言，该方法为检查淀粉样蛋白的构象菌株提供了一种新工具。