Biophysical Properties of the Fibril Structure of the Toxic Conformer of Amyloid-beta 42: Characterization by Atomic Force Microscopy in Liquid and Molecular Docking

Alzheimer's disease is associated with the aggregation of the misfolded neuronal peptide, amyloid-beta 42 (A beta 42). Evidence has suggested that several reasons are responsible for the toxicity caused by the aggregation of A beta 42, including the conformational restriction of A beta 42. In this study, one of the toxic conformers of A beta 42, which contains a Glu-to-Pro substitution (E22P-A beta 42), was explored using atomic force microscopy and molecular docking to study the aggregation dynamics. We proposed a systematic model of fibril formation to better understand the molecular basis of conformational transitions in the A beta 42 species. Our results demonstrated the formation of amorphous aggregates in E22P-A beta 42 that are stem-based, network-like structures, while the formation of mature fibrils occurred in the less toxic conformer of A beta 42, E22-A beta 42, that are sphere-like flexible structures. A comparison was made between the biophysical properties of E22P-A beta 42 and E22-A beta 42 that revealed that E22P-A beta 42 had greater stiffness, dihedral angle, number of beta sheets involved, and elasticity, compared with E22-A beta 42. These findings will have considerable implications toward our understanding of the structural basis of the toxicity caused by conformational diversity in A beta 42 species.