(432a) Computer Simulation of Protein Aggregation Kinetics Using An Intermediate Resolution Model

The aggregation of proteins into fibrillar structures is a symptom of over forty known human neurodegenerative diseases including Alzheimer's, Huntington's, and the prion diseases. Computer simulations allow us to study aggregation behavior on a molecular level. We combine an intermediate resolution protein model, PRIME, which captures the essential physical features and interactions of proteins, including realistic protein geometry, hydrogen bonding and hydrophobic interactions, with discontinuous molecular dynamics, a fast alternative to traditional molecular dynamics. Our objective is to identify and quantify the early stages of protein aggregation since association of small groups of peptides into oligomers is believed to be a key event in the onset of Alzheimer's disease. Current work in this area suggests that the peptides follow a nucleated reaction mechanism, which starts with free monomers that form small intermediate structures that are unstable and energetically unfavorable. These intermediates eventually reach a critical size, called the nucleus, which then grows through energetically favorable steps into larger structures known as fibrils. We chose polyalanine (A) as our model system since it is a simple peptide that is easy to model and it forms fibrillar structures in vitro at moderate peptide concentrations. Simulations of a system containing 192 KA₁₄K peptide chains were performed at peptide concentrations of 5 and 10 mM and reduced temperatures of T* = 0.125, 0.13, 0.135, and 0.14. Population data on the various types of small intermediate structures formed, including free monomers, small beta sheets consisting of hydrogen-bonded peptides, and fibrils consisting of hydrophobically stacked beta sheets, were recorded as a function of time. A mathematical model based on a proposed set of reversible association interactions was constructed. The population data gathered from the simulations is used to determine kinetic rate constants in the mathematical model. This optimized mathematical model provides information about the formation of the fibrillization nucleus and the growth of the fibril structure.