Computational study of the structure, dynamics and activity of an Alzheimer's amyloid beta-peptide

The aim of this work is to study the structure, dynamics and activity of the Alzheimer's Aβ peptide. Alzheimer's Disease (AD), the main cause of senile dementia, is the fourth leading cause of death among the elderly population. The formation of degenerative neuronal plaques is present in all cases of AD. The main component of these plaques is the Aβ peptide. A naturally occurring mutant of the Aβ peptide, in which one glutamate residue has been substituted by a glutamine, known as “Dutch” mutant, shows an increase in aggregation activity. It is important to understand the mechanism that leads to the aggregation of the peptide into plaques, to determine how the solution phase structure of the monomeric peptide influences the peptide deposition, and to establish the correlation between the peptide sequence and its activity.; In this dissertation a mechanism for elongation of the amyloid fibril is presented. The results of the molecular dynamics simulation of the Aβ(10–35)-NH ₂ wild type (WT) peptide and the “Dutch mutant” Aβ(10–35)-NH ₂E22Q, in aqueous solution, are described. The structure and the dynamics of the peptides are analyzed. Comparison of calculated and experimentally measured observables shows that the computational model is able to capture the structural and dynamical behavior of the solvated peptide. The results of our study support the conclusions that (1) the E22Q mutant peptide and WT peptide are both stable in a collapsed coil conformation, (2) the E22Q mutant peptide is more flexible than the WT peptide, and (3) the structure of the water in the first solvation shell is altered such that the solvent-peptide interaction energy is less attractive for the E22Q mutant than for the WT peptide. To explore the role of the solvent in the process of aggregation, we analyze the structural and dynamical properties of the water molecules at the solvent-peptide interface. The results found suggest that in the process of deposition of the peptide onto the fibril, the desolvation step might be responsible for the different activity showed by these two peptide congeners.