Laboratory for Atomistic and Molecular Mechanics, Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave. Room 1-235A&B, Cambridge, MA, USA.
Nanoscale. 2011 Apr;3(4):1748-55. doi: 10.1039/c0nr00840k. Epub 2011 Feb 23.
Amyloids are highly organized protein filaments, rich in β-sheet secondary structures that self-assemble to form dense plaques in brain tissues affected by severe neurodegenerative disorders (e.g. Alzheimer's Disease). Identified as natural functional materials in bacteria, in addition to their remarkable mechanical properties, amyloids have also been proposed as a platform for novel biomaterials in nanotechnology applications including nanowires, liquid crystals, scaffolds and thin films. Despite recent progress in understanding amyloid structure and behavior, the latent self-assembly mechanism and the underlying adhesion forces that drive the aggregation process remain poorly understood. On the basis of previous full atomistic simulations, here we report a simple coarse-grain model to analyze the competition between adhesive forces and elastic deformation of amyloid fibrils. We use simple model system to investigate self-assembly mechanisms of fibrils, focused on the formation of self-folded nanorackets and nanorings, and thereby address a critical issue in linking the biochemical (Angstrom) to micrometre scales relevant for larger-scale states of functional amyloid materials. We investigate the effect of varying the interfibril adhesion energy on the structure and stability of self-folded nanorackets and nanorings and demonstrate that these aggregated amyloid fibrils are stable in such states even when the fibril-fibril interaction is relatively weak, given that the constituting amyloid fibril length exceeds a critical fibril length-scale of several hundred nanometres. We further present a simple approach to directly determine the interfibril adhesion strength from geometric measures. In addition to providing insight into the physics of aggregation of amyloid fibrils our model enables the analysis of large-scale amyloid plaques and presents a new method for the estimation and engineering of the adhesive forces responsible of the self-assembly process of amyloid nanostructures, filling a gap that previously existed between full atomistic simulations of primarily ultra-short fibrils and much larger micrometre-scale amyloid aggregates. Via direct simulation of large-scale amyloid aggregates consisting of hundreds of fibrils we demonstrate that the fibril length has a profound impact on their structure and mechanical properties, where the critical fibril length-scale derived from our analysis of self-folded nanorackets and nanorings defines the structure of amyloid aggregates. A multi-scale modeling approach as used here, bridging the scales from Angstroms to micrometres, opens a wide range of possible nanotechnology applications by presenting a holistic framework that balances mechanical properties of individual fibrils, hierarchical self-assembly, and the adhesive forces determining their stability to facilitate the design of de novo amyloid materials.
淀粉样蛋白是高度组织化的蛋白质丝，富含β-折叠二级结构，可自组装形成严重神经退行性疾病（如阿尔茨海默病）影响的脑组织中的致密斑块。除了具有出色的机械性能外，淀粉样蛋白还被鉴定为细菌中的天然功能材料，它们也被提议作为纳米技术应用中新型生物材料的平台，包括纳米线、液晶、支架和薄膜。尽管在理解淀粉样蛋白结构和行为方面取得了最新进展，但潜在的自组装机制以及驱动聚集过程的基础粘附力仍知之甚少。基于以前的全原子模拟，我们在这里报告了一个简单的粗粒模型来分析粘附力和弹性变形之间的竞争。我们使用简单的模型系统来研究纤维原纤维的自组装机制，重点研究自折叠纳米轨道和纳米环的形成，从而解决将生物化学（埃）与与功能淀粉样蛋白材料的更大规模状态相关的微米尺度联系起来的关键问题。我们研究了改变纤维间粘附能对自折叠纳米轨道和纳米环结构和稳定性的影响，并证明即使纤维-纤维相互作用较弱，这些聚集的淀粉样蛋白纤维在这些状态下也是稳定的，只要构成的淀粉样蛋白纤维长度超过几百纳米的临界纤维长度尺度。我们进一步提出了一种从几何测量直接确定纤维间粘附强度的简单方法。除了深入了解淀粉样蛋白纤维聚集的物理特性外，我们的模型还能够分析大规模淀粉样蛋白斑块，并提出了一种新方法来估计和设计负责淀粉样蛋白纳米结构自组装过程的粘附力，填补了以前在主要超短纤维的全原子模拟和更大的微米级淀粉样蛋白聚集体之间存在的空白。通过对由数百根纤维组成的大规模淀粉样蛋白聚集体的直接模拟，我们证明了纤维长度对其结构和力学性能有深远的影响，我们对自折叠纳米轨道和纳米环的分析得出的临界纤维长度尺度定义了淀粉样蛋白聚集体的结构。这里使用的多尺度建模方法跨越了从埃到微米的尺度，通过提供平衡单个纤维的机械性能、层次自组装和决定其稳定性的粘附力的整体框架，为新兴的淀粉样蛋白材料的设计开辟了广泛的纳米技术应用可能性。
