Molecular Dynamics Simulation of Protein Aggregation
Date: Sept. 20
Place: Broun 239
Time: 3:30 p.m.
 |
|
Dr. Carol Hall |
Carol K. Hall
Alcoa Professor of Chemical and Biomolecular Engineering
Hall is Alcoa Professor of Chemical and Biomolecular Engineering at North Carolina State University. This National Academy of Engineering member received her bachelors in physics from Cornell University and her doctorate in physics from the State University of New York at Stony Brook. After postdoctoral training in the Chemistry Department at Cornell and a brief stint as an economic modeler at Bell Laboratories, she joined the Chemical Engineering Department at Princeton University in 1977 as one of the first women to be appointed to a chemical engineering faculty in the U.S. In 1985 she joined the Chemical Engineering Department at North Carolina State University.
Hall's research focuses on applying statistical thermodynamics and molecular-level computer simulation to topics of chemical engineering interest involving macromolecules or complex fluids. Her approach is based on developing simple molecular models that reveal the fundamental principles and essential features that underlie complex physical phenomena. She and her coworkers William Russel and then-student Alice Gast were the first to demonstrate that statistical thermodynamics, which is normally used to describe the behavior of molecules, could also be used to describe the behavior of micron-sized (colloidal) particles. She developed the Generalized Flory Dimer equation of state for chain-like molecules and co-developed the Hall-Helfand correlation function for polymer conformational relaxation. Her recent work concerns the formation of ordered protein aggregates called amyloid fibrils, a cause or associated symptom of Alzheimer's, Parkinson's and the prion diseases (e.g., Mad Cow disease). She has authored over 170 publications.
Carol Hall has received many honors and awards, the most recent of which are the NCSU Alumni Association Distinguished Graduate Professor Award, the Texas Distinguished Faculty Lecturer, the Case Western Robert J. Adler Memorial Lecturer, the Grace Hopper Lecturer at the University of Pennsylvania, and the NCSU R. J. Reynolds Tobacco Company Award. She will be the Insititute Lecturer at the upcoming AIChE meeting in San Francisco. Hall is on the editorial board of six scientific journals and is a Fellow of the AICHE.
ABSTRACT
Molecular Dynamics Simulation of Protein Aggregation
Protein aggregation is a cause or associated symptom of a number of neurodegenerative diseases including Alzheimer's, Parkinson's and prion disease. It can also interfere with the recovery of recombinant proteins during processing and can limit the stability of protein-based drugs during their packaging, shipping, storage and administration.
We are engaged in a computational study aimed at understanding the basic physical principles that govern the competition between protein aggregation and protein folding. A novel off-lattice, intermediate-resolution protein model, PRIME, has been developed that is simple enough to allow the simulation of multi-protein systems over relatively long time scales, yet contains enough genuine protein-like character to mimic real protein dynamics when used in conjunction with constant-temperature discontinuous molecular dynamics, a fast alternative to conventional molecular dynamics.
We are using PRIME to investigate the formation and properties of fibrillar protein aggregates, the structures that have been implicated in the pathology of many neurodegenerative diseases including Alzheimer's and Parkinson's diseases. Simulations have been performed on systems containing 12 to 96 model polyalanine peptides, each containing 16 residues. Polyalanine was chosen for study because synthetic polyalanine-based peptides, which form a-helical structures at low temperatures and low peptide concentrations, have been found to form b-sheet complexes (fibrils) in vitro at high temperatures and high peptide concentrations [2].
In our simulations we find that at a low peptide concentration, a system of peptides initially in the random coil state forms alpha-helices at low temperatures and assembles into large beta-sheet structures at high temperatures. When the concentration is increased at high temperatures, the system again forms beta-sheets but these assemble into fibrils as the simulation progresses. The effect of temperature, peptide concentration and chain length on the kinetics and thermodynamics of fibril formation is being explored. Movies of the simulation will be shown.
