title: Self-folding and aggregation of amyloid nanofibrils.
abstract: 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.
authors.affiliation: 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.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Paparcone
authors.forename: Steven W
authors.initials: SW
authors.lastname: Cranford
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Buehler
mesh_terms: D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure*; D003198:Computer Simulation; D008956:Models, Chemical; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000648:ultrastructure; D049329:Nanostructures / Q000737:chemistry* / Q000648:ultrastructure*; D011487:Protein Conformation; D017510:Protein Folding
chemical_list: D000682:Amyloid; D046912:Multiprotein Complexes