| Multiple human diseases including Alzheimer's, Parkinson's, Huntington's, and Type II diabetes are associated with the aggregation of proteins. The postmortem cells of patients afflicted with such diseases exhibit insoluble amyloid plaques deposited within the cells. There is mounting evidence from recent investigations that the main toxic species in these diseases are the prefibrillar oligomers of the proteins that are specific to each disease. A deeper understanding of the structure and formation process of the oligomeric intermediates would provide useful insights for the development of potentially useful therapeutic strategies. However these intermediates are highly unstable and thus extremely difficult to study using experimental techniques. In this thesis, we have tried to outline how these events can be investigated using computer simulations. In particular we present three important methods. First, we present a novel Monte Carlo method to determine the actual free energy change associated with the misfolding process; second, we present a transition path sampling algorithm to study the actual dynamics of aggregation and third, we present a method to study the interaction of the disease proteins with cell membrane. The techniques developed in this work were applied to understand the misfolding and aggregation of proteins involved in Type II diabetes, Huntington's disease, Alzheimer's disease and Prion disease. |
