Abstract
Study of neurodegenerative diseases is an important issue because of their high occurring rates all these years. Many reports indicated that neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease are all caused by abnormal protein aggregation. Type II diabetes is not a neurodegenerative disease, but its abnormal insulin aggregation can increase the probability of neurodegenerative diseases. It is still not clear how do these proteins assemble and lose their function in vivo. In this thesis I’ll report our results about polyglutamine and insulin aggregation from molecular dynamics simulation. Aggregation of polyglutamine and insulin have been proved as the cause of several human diseases, in particular to Huntington’s disease and diabetes. Molecular dynamics simulation in silico let scientists able to reach the experimental environment which protein can aggregate immediately and observe protein aggregation process under nanosecond time scale. To study how polyglutamine aggregate and form β-sheets, we employed replica-exchange molecular dynamics to simulate one and two polyglutamine peptides with ten glutamine residues. It is the first time that polyglutamine peptides are simulated by all-atom force field replica-exchange molecular dynamics accompanied with explicit water molecules. Our results show that the structures of two polyglutamine peptides are changed depending on their inter-peptide distance. When the inter-peptide distance between two polyglutamine peptides is large, two peptides formed helix or coil structures as in the case of one chain. While the inter-peptide distance decreases, the intra-peptdie β-sheet structures appear as an intermediate state occasionally, and become the inter-peptide β-sheets in the end. We also found that the polyglutamine dimer tends to form the anti-parallel β-sheet conformations rather than the parallel one, which is consistent with previous experiments. In my second project, I employed united atom force field molecular dynamics with explicit water molecules to simulate insulin monomer, which is larger than polyglutamine peptide. Previous research indicated that insulin formed amyloid fibril via stacking on the peptide LVEALYL. LVEALYL is the fragment B11-17 of insulin, it is binding well with insulin. Our results shows that two LVEALYL peptides could aggregate as a β-sheet. By molecular mechanic Poisson-Boltzmann surface area (MM/PBSA) method we estimated the binding free energy of LVEALYL to insulin, the result of strong binding affinity is consistent with the previous research. We also found a peptide RGFFYT, the fragment B22-27 of insulin, can aggregate and bind to insulin monomer, too. In our results we showed that RGFFYT has comparable binding affinity to insulin as LVEALYL.