The Relationship Between the Number of Residues in the Dynamics and Stability of the A-Beta Amyloid, a Molecular Dynamics Study

Abstract

Alzheimer's disease has been identified as a progressive, neurodegenerative disorder associated with protein misfolding due to the aggregation of monomeric beta-amyloid proteins (A-beta) to form fibrillar plaques. Experimental attempts to purify and chemically analyze the structure of A-beta protofibrils and to elucidate the mechanism of fibril formation have yet to reveal much about the molecular etiology of AD, due to the low solubility and non-crystalline nature of A-beta. Experimentally, it is shown that the 43-residue strand of A-beta has higher cytotoxicity than the 40 or 42 strands. To better understand the relationship between the number of residue and the fibril-forming propensity of the peptide we have ran several all atom explicit water molecular dynamics simulations of A-beta strands of 40, 42, and 43 residues starting from their NMR structures. Overall, our simulations shows a transition of existing alpha helices to 3(10)- or pi-helices in agreement with experimental data. Our simulation of A-beta 40 and 42 residue strands confirms the substantial shift of secondary structure formation due to the additional two residues. However, it is interesting that the addition of the 43rd residue (threonine) only cause a small secondary structure change in the A-beta strand of 42 residues. Therefore it seems that the residues 41 and 42 are more important in secondary structure formation than the residue 43.