Spontaneous Formation of Oligomers and Fibrils in Large Scale Molecular Dynamics Simulations of the Alzheimer’s Peptides

Abstract: Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer’s, Parkinson’s and the prion diseases.  While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large scale molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers of peptides. The simulations are fast enough to enable us to follow the steps in the aggregation process from an initial configuration of random coils to oligomers and then to proto-filaments with cross-β structures. In simulations of Aβ17-42 peptides we uncovered two fibrillization mechanisms that govern their structural conversion from disordered oligomers into protofilaments.  We also investigate the influence of crowding agents on oligomerization and fibrillization for Aβ16-22. Simulations are conducted which allow examination of the impact of naturally-derived inhibitors (resveratrol, curcumin, vanillin, and curcumin) on the oligomerization and fibrillation of Aβ17-36. Movies of the aggregation process on a molecular level will be shown.

Biography: Professor Carol K. Hall is the Camille Dreyfus Distinguished University Professor of Chemical and Biomolecular Engineering at North Carolina State University. She received her B.A. in physics from Cornell University and her Ph.D. in physics from the State University of New York at Stony Brook.  After postdoctoral training in the Chemistry Department at Cornell and a brief period 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, biological or engineering interest involving macromolecules, soft matter and complex fluids.  Current research topics include protein folding/aggregation, multipolar colloids, protein or peptide design, and remediation of microplastic pollution.  The author of over 290 publications, she is a recipient of the AIChE 2015 Founders Award and the 2019 John M Prausnitz Award from the  PPEPPD Thermodynamics Conferences. She is a Fellow of the American Institute of Chemical Engineers, the American Physical Society and the American Association for the Advancement of Science. In 2020 she was awarded the AIChE Margaret Hutchinson Rousseau Pioneer Award for Lifetime Achievement by a Woman Chemical Engineer. Hall was elected to the National Academy of Engineering in 2005 and now serves as its Home Secretary.