Assembly of normally soluble proteins into ordered aggregates, known as amyloid fibrils, is a cause or associated symptom of numerous human disorders, including Alzheimer's and the prion diseases. The fibrils found in Alzheimer's disease are primarily composed of the 39-43 amino acid peptide, beta-amyloid. Recent experimental studies have offered tantalizing clues regarding the fibril structure adopted by beta-amyloid, but our understanding of its assembly is still far from complete. The long term goal of our work is to determine the underlying physical forces responsible for the misfolding and aggregation of proteins. Our objective is to extend the intermediate-resolution protein model, PRIME (Protein Intermediate Resolution Model) that we have already developed for polyalanine to the description of beta-amyloid. PRIME is well suited for modeling protein aggregation because it provides a faithful representation of protein geometry while also capturing the essential features of the forces responsible for protein folding, hydrogen bonding and hydrophobicity.

We are using a two-pronged approach in the modeling of beta-amyloid. One model attempts to capture the basic physical features of beta-amyloid using a simple single-sphere side chain representation and an “HP” model description of the energetics of each side chain. The second model characterizes specific side chain interactions essential to the aggregation of beta-amyloid using either a one-or-two-sphere side chain representation and an “HP” + electrostatic interaction description of the energetics of each side chain. We explore how variations in the temperature, concentration, hydrophobic strength, and quench rate affect the formation and structure of beta-amyloid. Movies will be shown of the aggregation process.