Computer Simulation Of Protein Aggregation Kinetics Using An Intermediate Resolution Model
Erin M. Phelps, Department of Chemical and Biomolecular Engineering, North Carolina State University, College of Engineering 1, Box 7905, 911 Partners Way, Raleigh, NC 27695 and Carol K. Hall, Department of Chemical and Biomolecular Engineering, North Carolina State University, Engineering Building I, Box 7905, 911 Partners Way, Raleigh, NC 27695.
Protein aggregation into fibril structures is a symptom of over twenty 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. Our group uses an intermediate resolution protein model, PRIME, which captures the essential physical features and interactions of real proteins, such as hydrogen bonding and the hydrophobic effect. Discontinuous molecular dynamics is used in conjunction with PRIME so that we can obtain long time scale simulation results in a reasonable time frame (days) rather than the months it takes for all-atom representations using traditional molecular dynamics. This project focuses on the kinetics of fibril formation; it is an attempt to identify and quantify the reaction mechanism underlying the aggregation process. Multiple simulations of a system of 96, 144, and 192 KA14K peptide chains were performed covering a range of concentrations including 2.5, 5, 7.5, and 10 mM, at reduced temperatures of T* = 0.125, 0.13, 0.135, and 0.14. A mathematical model was constructed to represent a proposed nucleation reaction mechanism. The simulations produced population data which was used to determine kinetic rate constants in the mathematical model. This optimized mathematical model allows us to identify the rate limiting step in the aggregation formation process and provides information about the nucleus.