Abstract
This study provides critical insights into the role of surface-mediated processes in Alzheimer's disease, with implications for the aggregation of Abeta42 peptides. Employing coarse-grained molecular dynamics simulations, we focus on elucidating the molecular intricacies of these processes beyond primary nucleation. Central to our investigation is the analysis of a freely diffusing Abeta42 monomer on preformed fibril structures. We conduct detailed calculations of the monomer's diffusion coefficient on fibril surfaces (as a one-dimensional case), along with various monomer orientations. Our findings reveal a strong and consistent correlation between the monomer's diffusion coefficient and its orientation on the surface. Further analysis differentiates the effects of parallel and perpendicular alignments with respect to the fibril axis. Additionally, we explore how different fibril surfaces influence monomer dynamics by comparing the C-terminal and N-terminal surfaces. We find that the monomer exhibits faster diffusion coefficients on the C-terminal surface. Differences in surface roughness (S(R)), quantified using root-mean-square distances, significantly affect monomer dynamics, thereby influencing its diffusion on the surface. Importantly, this study underscores that fibril twisting acts as a regulatory niche, selectively influencing these orientations and their diffusion properties necessary for facilitating fibril growth within biologically relevant time scales. This discovery opens new avenues for targeted therapeutic strategies aimed at manipulating fibril dynamics to mitigate the progression of Alzheimer's disease.