Stability and Structure of Amyloid-Forming Peptides from Computer Simulation

The aggregation of monomeric proteins/peptides to form ordered amyloid oligomers and fibrils is a pathogentic feature of many human degenerative diseases including Alzheimer's Parkinson's, Huntington's, and prion diseases. Despite of significant progress, the structure of the early oligomeric species on the aggregation pathways remains unknown at an atomic level of detail. Knowledge of the structure of these oligomers is essential for understanding the process of pathology of the amyloidoses and for the rational design of drugs to against amyloid formation. A systemic analysis of preformed oligomeric structures is performed to examine their sequence and structural characteristics. We identify several stable oligomeric structures with different structural morphology, size, and shape, delineate several common features in amyloid organizations and amyloid structures, and illustrate aggregation driving forces that stabilize these oligomeric structures using computational simulations. The structural comparison among different oligomers suggests that the aggregation mechanism leading to distinct morphologies and the aggregation pathways is sequence specific due to differences in side-chain packing arrangements, intermolecular driving forces, sequence composition, and residue positions.