(638c) Computer Simulation of Protein Aggregation 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. Recent experimental studies have offered tantalizing clues regarding the fibril structure, 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 mis-folding and aggregation of proteins, specifically the beta-amyloid peptide linked to Alzheimer's. Our objective is to extend the intermediate-resolution protein model, PRIME (Protein Intermediate Resolution Model) that we have developed for alanine to the description of all twenty amino acids. 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 extended PRIME to the description of all twenty amino acids (PRIME 20) using a two-pronged approach, focusing on both the protein geometry and energetics. In PRIME 20, each amino acid has a single-sphere side chain with a unique diameter and C-alpha?side chain bond length. Each amino acid is sorted into one of seven classes resulting in twelve interaction types, including both strong and weak attractive, covalent, repulsive, charged, polar and hydrogen bonding. We explored how variations in temperature, concentration, and quench rate affect the formation and structure of several simple peptide sequences known to aggregate. Additionally, we apply PRIME 20 to the beta-amyloid peptide to determine how well it captures this complex aggregation process.