Exploring Abeta42 Monomer Diffusive Dynamics on Fibril Surfaces through Molecular Simulations

Abstract

AbstractAlzheimer’s disease is closely linked to the aggregation of Abeta42 peptides, which follow a complex pathway involving primary nucleation and secondary processes. While previous research has underscored the importance of secondary processes, this study employs molecular dynamics simulations to delve into their molecular-level intricacies. We employ coarse-grained molecular dynamics with a freely diffusing Abeta42 monomer alongside a pre-formed fibril structure. We conducted comprehensive calculations of the monomer’s diffusion coefficient (D) on the fibril surface, considering both straight and twisted fibril structures, as well as various monomer surface orientations. Notably, our findings reveal a robust correlation between the monomer’s diffusion coefficient (D) and its surface orientation, irrespective of the degree of fibrillar twisting. Additional analysis of monomer orientation further reinforces the orientation-dependent diffusion results, distinguishing between parallel and perpendicular alignments. Additionally, we explore how distinct fibril surfaces influence monomer dynamics. We compared the C-terminal and N-terminal surfaces and found that the monomer exhibits lower diffusion coefficients (D) on the N-terminal surface. Surface roughness, quantified using root-mean-square deviation (RMSD), revealed significant differences between these surfaces. The dissimilarity in shape and roughness contributes to the observed differences in monomer dynamics, highlighting the role of surface characteristics in molecular-level aggregation.