Residue-Specific Dynamics and Local Environmental Changes in Aβ40 Oligomer and Fibril Formation

Elucidating local dynamics of protein aggregation is crucial for understanding the mechanistic details of protein amyloidogenesis. Herein, we studied the residue-specific dynamics and local environmental changes of A beta 40 along the course of aggregation by using para-cyanophenylalanine (Phe(CN)) as a fluorescent and vibrational probe. Our results show that the Phe(CN) residues introduced at various positions all exhibited an immediate decay of fluorescence intensity, indicating a relatively synergistic process in early oligomer formation. The fast decreases in the fluorescence intensities of residues19 and 20 in the central hydrophobic core region and residue10 in the N-terminal region suggest that they play crucial roles in the formation of the oligomeric core. The Phe(CN)4 residue exhibits a remarkably slower decrease in fluorescence intensity, implicating its dynamic conformational characteristics in oligomer and fibril formation. Our results also suggest that the N-terminal residues in fibrils are surrounded by a relatively hydrophobic local environment, as opposed to being solvated.