Unravelling the Complexity of Amyloid Peptide Core Interfaces

Amyloids, large intermolecular sandwiched β-sheet
structures,
underlie several protein misfolding diseases but have also been shown
to have functional roles and can be a basis for designing smart and
responsive nanomaterials. Short segments of proteins, called aggregation-prone
regions (APRs), have been identified that nucleate amyloid formation.
Here we present the database of 173 APR crystal structures currently
available in the PDB, and a tool, ACW, for analyzing their topologies
and the 267 inter-β-sheet interfaces of zipper regions assigned
in these structures. We defined a new descriptor of zipper interfaces,
the surface detail index (SDi), which quantifies the intertwining
between the side chains of both β-sheets of the zipper, an important
factor for the molecular recognition and self-assembly of these mesostructures.
This allowed a comparative analysis of the zipper interfaces and identification
of 6 clusters with different intertwining, steric fit, and size characteristics
using three complementary descriptors, SDi, shape complementarity,
and buried surface area. 60% of the APR structures are formed by parallel
β-sheets, of which 52% belong to the topological class 1. This
could be explained by the better fit and a deeper entanglement of
the zipper regions of the parallel structures than of the antiparallel
structures, as the analysis showed that both their shape complementarity
(0.79 vs 0.70) and SDi (1.53 vs 1.32) were higher. The higher abundance
of certain residues (Asn and Gln in parallel and Leu and Ala in antiparallel
β-sheets) can be explained by their ability to form different
ladder-like secondary interaction patterns within β-sheets.
Analogous to the hierarchy of protein structure, we interpreted the
primary, secondary, tertiary, and quaternary structure levels of APRs
revealing different characteristics of the zipper regions for both
parallel and antiparallel β-sheet structures, which may provide
clues to the structural conditions of amyloid core formation and the
rational design of amyloid polymorphs.

淀粉样蛋白（Amyloids）作为一类大型分子间夹合β折叠结构，既是多种蛋白质错误折叠疾病的病理基础，同时也被证实具备功能性应用价值，可作为智能响应型纳米材料的设计基础。蛋白质的短片段——即被称为易聚集区域（aggregation-prone regions, APRs）——已被证实可作为淀粉样蛋白聚集的成核位点。本研究构建了收录蛋白质数据库（Protein Data Bank, 下文简称PDB）中现有173个APR晶体结构的数据集，并开发了一款名为ACW的分析工具，用于解析这些结构的拓扑特征，以及其中267个已标注的拉链区域的β折叠间界面信息。我们针对拉链界面定义了一项全新的描述参数——表面细节指数（surface detail index, SDi），该参数可量化拉链结构中两条β折叠侧链的缠绕程度，而这一因素正是影响这类介观结构分子识别与自组装的关键调控因素。基于该参数，我们得以对拉链界面开展系统性对比分析，并通过表面细节指数、形状互补性与埋藏表面积这三个互补性描述参数，将所有拉链界面划分为6个具备不同缠绕程度、空间适配性与尺寸特征的聚类簇。60%的APR晶体结构由平行β折叠构成，其中52%隶属于拓扑分类1级。研究表明，平行结构的拉链区域相比反平行结构具备更优异的空间适配性与更深的侧链缠绕程度，这可解释其高占比现象：平行结构的形状互补性（0.79 vs 0.70）与表面细节指数（1.53 vs 1.32）均显著更高。部分氨基酸残基的丰度差异也可得到合理解释：平行β折叠中富集天冬酰胺（Asn）与谷氨酰胺（Gln），而反平行β折叠中则以亮氨酸（Leu）与丙氨酸（Ala）为主，这源于这些氨基酸可在β折叠内部形成不同的阶梯状二级相互作用模式。类比蛋白质结构的层级划分体系，我们对APRs的一级、二级、三级与四级结构层次进行了解析，揭示了平行与反平行β折叠结构中拉链区域的差异化特征，这可为淀粉样核心形成的结构条件解析以及淀粉样多态体的理性设计提供重要理论线索。