(24b) Computer Simulation of Fibril Forming Peptides with an Intermediate Resolution Protein Model

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, Aβ. Recent experimental studies have offered tantalizing clues regarding the fibril structure adopted by Aβ, 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 the protein, Aβ. 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 apply discontinuous molecular dynamics (DMD) to PRIME models of Aβ(16-22), Aβ(10-40), and Aβ(10-42) to study the assembly of systems containing 12 to 48 peptides into ordered structures. Currently, we are exploring how variations in the temperature, concentration, hydrophobic strength, and quench rate affect the formation and structure of Aβ. Movies will be shown of the aggregation process.