| A number of disorders are associated with the deposition of a variety insoluble protein aggregates. A great deal of evidence has led to the hypothesis that there exists a commonality between the aggregation processes of this diverse body of proteins and peptides. Understanding the universally applicable factors which influence the formation and stability of protein aggregates will provide a better understanding of the diseases to which they lead. To this end, we study several intrinsic and environmental factors which influence protein aggregation, including the role of water, the amount of frustration inherent in the individual proteins, confinement, and protein-surface interactions.; The interactions within and among a specific protein also have a strong influence on how that protein self assembles. Therefore, we study the Amyloid-beta peptide (A beta) associated with Alzheimer's disease (AD). A beta forms ordered fibrillar aggregates which combine to produce senile plaques, the hallmark of AD. Although the precise role of fibrils in AD remains unclear, fibril deposition is likely to at least be a contributing factor in AD etiology. In light of this, amyloid fibril inhibitor molecules have been developed, yet the precise mechanism by which they operate has not been explained. Here, we investigate the way in which the N-methylated A beta (16-20m) peptide binds to a model amyloid fibril inhibiting further growth, as well as its role in preventing fibril formation by binding to A beta monomers. We also study familial forms of AD which arise from single amino acid mutations in A beta. These mutations cause distinct fibrillogenic properties, and generally alter the amounts or aggregation properties of A beta. In particular, we investigate how these mutations alter the monomer structure and provide insight to the aggregation process leading to familial AD. Through our computational studies we seek an understanding of protein aggregation both in a detailed, disease-oriented, sense through the study of A beta as well as in a global sense by investigating the effects of various factors influencing protein aggregation. |
