Structural Conversion of Aβ17-42 Peptides from Disordered Oligomers to U-Shape Protofilaments via Multiple Kinetic Pathways.
Structural Conversion of Aβ17-42 Peptides from Disordered Oligomers to U-Shape Protofilaments via Multiple Kinetic Pathways.
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DOI：
10.1371/journal.pcbi.1004258
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发表时间：
2015-05
影响因子：
4.3
通讯作者：
Chang I
中科院分区：
文献类型：
--
作者：
Cheon M;Hall CK;Chang I
发现蛋白质聚集成纤维的机制是理解阿尔茨海默氏症和帕金森氏症等神经退行性疾病的分子水平过程的重要第一步。这项工作的目标是提供对淀粉样β肽从单体转化为寡聚体再转化为原纤维的动力学途径的结构变化的见解。通过对PRIME 20（一种旨在捕获蛋白质聚集的化学和物理方面的力场）应用不连续分子动力学模拟，我们已经能够追踪包含8个Aβ17-42肽的系统的整个聚集过程。我们发现了两种控制Aβ17-42肽从无序寡聚体到原丝的结构转化的纤维化机制。第一种机制是以U形寡聚核为模板的单体转化为U形原丝。第二种机制涉及一个长寿命和途径亚稳态寡聚体与S形链，具有C-末端转向，途中最终U形原丝。在最近的实验中，具有这种C-末端转向的寡聚体被认为是阿尔茨海默病中细胞毒性的主要贡献因素。从我们的PRIME 20/DMD模拟的U形原丝的内部结构一致，以及从固态NMR实验。这里提出的方法提供了一个简单的分子水平的框架来描述一般的蛋白质聚集和可视化的动力学演变的一个假定的有毒元素在阿尔茨海默氏症特别。了解蛋白质的折叠和聚集机制对于阐明蛋白质及其复合物的生物学功能具有重要意义。基于生物物理学的思想和超级计算能力的提高，我们描述蛋白质折叠的能力已经取得了许多进展，但真实模拟蛋白质聚集的整个动力学过程，包括原纤维形成，仍然是生物物理学和计算生物学中具有挑战性的任务。这项工作描述了我们在分子水平上模拟蛋白质聚集的能力的突破，以及导致阿尔茨海默病等神经退行性疾病的有毒物质的出现。基于这项工作，人们现在可以追踪从无序单体到亚稳定寡聚体到原丝，然后是淀粉样纤维的整个聚集过程。这是一个显着的进步，在目前的技术水平，在生物物理学和计算生物学揭示的基本机制背后的淀粉样蛋白原纤维形成的聚集倾向的蛋白质。
Discovering the mechanisms by which proteins aggregate into fibrils is an essential first step in understanding the molecular level processes underlying neurodegenerative diseases such as Alzheimer’s and Parkinson's. The goal of this work is to provide insights into the structural changes that characterize the kinetic pathways by which amyloid-β peptides convert from monomers to oligomers to fibrils. By applying discontinuous molecular dynamics simulations to PRIME20, a force field designed to capture the chemical and physical aspects of protein aggregation, we have been able to trace out the entire aggregation process for a system containing 8 Aβ17–42 peptides. We uncovered two fibrillization mechanisms that govern the structural conversion of Aβ17–42 peptides from disordered oligomers into protofilaments. The first mechanism is monomeric conversion templated by a U-shape oligomeric nucleus into U-shape protofilament. The second mechanism involves a long-lived and on-pathway metastable oligomer with S-shape chains, having a C-terminal turn, en route to the final U-shape protofilament. Oligomers with this C-terminal turn have been regarded in recent experiments as a major contributing element to cell toxicity in Alzheimer’s disease. The internal structures of the U-shape protofilaments from our PRIME20/DMD simulation agree well with those from solid state NMR experiments. The approach presented here offers a simple molecular-level framework to describe protein aggregation in general and to visualize the kinetic evolution of a putative toxic element in Alzheimer’s disease in particular. Understanding the mechanisms of protein folding and aggregation is of fundamental importance in elucidating the biological function of proteins and their complex. Many advances have been made in our ability to describe protein folding based both on ideas from biophysics and improvements in supercomputing power, yet realistic simulations of the entire kinetic process of protein aggregation including fibril formation still remain challenging tasks in biophysics and computational biology. This work describes a breakthrough in our ability to simulate the aggregation of proteins on a molecular level and the emergence of the toxic species responsible for the cause of neuro-degenerative diseases such as Alzheimer’s disease. Based on this work, one can now trace the entire aggregation process starting from disordered monomers to meta-stable oligomers to protofilament and then amyloid fibril. This is a significant advance over the current state of the art in both biophysics and computational biology in uncovering the fundamental mechanisms behind the amyloid fibril formation for aggregation-prone proteins.
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影响因子：
2.9
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