Exploring Abeta42 Monomer Diffusion Dynamics on Fibril Surfaces through Molecular Simulations

This study provides critical insights into the role of surface-mediated secondary processes in Alzheimers disease, particularly regarding the aggregation of Abeta42 peptides. Employing coarse-grained molecular dynamics simulations, we focus on elucidating the molecular intricacies of these secondary processes beyond primary nucleation. Central to our investigation is the analysis of a freely diffusing Abeta42 monomer on pre-formed fibril structures. We conduct detailed calculations of the monomers 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 monomers 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 influencemonomer dynamics by comparing the C-terminal and N-terminal surfaces. We find that the monomer exhibits lower diffusion coefficients on the N-terminal surface. Differences in surface roughness (SR), quantified using root-mean-square distances, significantly affect monomer dynamics, thereby influencing the secondary aggregation process. Importanly, 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 Alzheimers disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/582685v3_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@f94f0eorg.highwire.dtl.DTLVardef@1b5362corg.highwire.dtl.DTLVardef@1f7aea9org.highwire.dtl.DTLVardef@1ec109f_HPS_FORMAT_FIGEXP M_FIG C_FIG