| A number of biologically active peptides have been identified as having the capacity to aggregate into insoluble fibrils characteristic of disease pathologies. Among these are human islet amyloid polypeptide (hIAPP), whose fibrillar aggregates are found in patients with type II diabetes, and the amyloid beta (Abeta) peptide, whose aggregates are associated with Alzheimer's disease. In the latter case, recent studies suggest that the key cytotoxic species associated with the initial onset of the disease are not the fibrils, but rather low molecular weight oligomeric aggregates of amyloidgenic peptides. In this study, we examine the stability and formation of amyloidgenic peptide oligomers using molecular dynamics simulations.;A complete characterization of the aggregation process should include an examination of intrinsic factors, such as the amino acid sequence, and extrinsic factors, such as concentration and ionic strength. To that end, we first examined the stability of beta--sheet dimers formed from the amyloidgenic peptide fragment hIAPP20--29 at varying peptide concentrations, as well as the non--amyloidgenic rat analog rIAPP 20--29 peptide. We investigated the formation of potential beta--sheet nucleation sites of hIAPP20--29 and rIAPP20--29 dimers at two concentrations. We then reexamined this potential for hIAPP20--29 under various ionic strength conditions.;In a separate study, we have probed the effect of confinement and hydration on peptide aggregation by simulating fragments of both the amyloidgenic Abeta peptide (Abeta16-22) and Sup35 peptide (Sup357--13 ) in an AOT/water reverse micelle environment in bulk isooctane. The results of our study are in qualitative agreement with recent experimental studies and suggest a detailed atomic level picture of the underlying interactions that stabilize the aggregated state.;Overall, our computational studies provide insight into the fundamental factors underlying both in vitro and in vivo peptide aggregation. |
