Network-Based Classification and Modeling of Amyloid Fibrils
Network-Based Classification and Modeling of Amyloid Fibrils
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DOI：
10.1021/acs.jpcb.9b03494
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发表时间：
2019-07-04
影响因子：
3.3
通讯作者：
Butts, Carter T.
中科院分区：
文献类型：
--
作者：
Grazioli, Gianmarc;Yu, Yue;Butts, Carter T.
淀粉样原纤维是在各种生理和体外条件下自组装的局部有序的蛋白质聚集体。它们的形成作为物理化学问题具有根本意义，并且在阿尔茨海默病、II型糖尿病和其他人类疾病中起着核心作用。随着已知的淀粉样蛋白原纤维结构的数量的增长，出现了对用于描述和分类原纤维类型的命名法以及引起这些结构的自组装的物理学的理论描述的需要。在这里，我们介绍了一个系统的命名和粗粒化的方法来描述的拓扑结构的原纤维和其他蛋白质聚集体，沿着与一个计算方法来模拟蛋白质聚集。两者都有图论和统计力学的数学基础，并与原纤维结构和聚集动力学的实验数据相一致。我们的图表示的原纤维拓扑结构使我们能够定义一个网络的基础上单体之间的连接模式，而不是详细的分子间相互作用的哈密顿量，大大加快了大型合奏的模拟。我们的模拟策略是能够概括的蛋白质数据库中发现的所有目前已知的淀粉样蛋白原纤维拓扑结构的形成，以及原纤维和低聚物的形成动力学。
Amyloid fibrils are locally ordered protein aggregates that self-assemble under a variety of physiological and in vitro conditions. Their formation is of fundamental interest as a physical chemistry problem and plays a central role in Alzheimer's disease, Type II diabetes, and other human diseases. As the number of known amyloid fibril structures has grown, the need has arisen for a nomenclature for describing and classifying fibril types, as well as a theoretical description of the physics that gives rise to the self-assembly of these structures. Here, we introduce a systematic nomenclature and coarse-graining methodology for describing the topology of fibrils and other protein aggregates, along with a computational methodology for simulating protein aggregation. Both have mathematical underpinnings in graph theory and statistical mechanics and are consistent with available experimental data on the fibril structure and aggregation kinetics. Our graph representation of the fibril topology enables us to define a network Hamiltonian based on connectivity patterns among monomers rather than detailed intermolecular interactions, greatly speeding up the simulation of large ensembles. Our simulation strategy is capable of recapitulating the formation of all currently known amyloid fibril topologies found in the Protein Data Bank, as well as the formation kinetics of fibrils and oligomers.