Seminar Series: Nonnative Protein Aggregation from a Multi-scale Biophysical & Modeling Approach
|Event Date:||October 23, 2007|
|Speaker:||Professor Christopher J. Roberts|
|Speaker Affiliation:||Dept. of Chemical Engineering, University of Delaware|
Non-native aggregation is a ubiquitous problem during biopharmaceutical product formulation and process development. The presence of even relatively small quantities of soluble or insoluble, nonnative aggregates may significantly increase product development time and expenses, raise regulatory concerns, and potentially jeopardize patient safety due to increased immunogenic responses. The process of nonnative aggregation has also garnered significant interest from the medical and life science communities due to its potential role in generating toxic intermediate- to high-molecular-weight oligomers implicated in a growing number of chronic diseases such as Huntington’s Disease, Alzheimer’s Disease, and prion diseases. Nonnative aggregation involves multiple, parallel and sequential levels or stages, including: (partial) unfolding or refolding of initially native or unfolded protein; nucleation or formation of the smallest aggregates that are (net) irreversible and often stabilized by b-sheet secondary structure motifs; aggregate growth via polymerization (monomer addition) and aggregate condensation or coalescence to form filaments, fibers, gels, and/or precipitates. Although much has been learned at a qualitative level about some stages of non-native aggregation, a number of fundamental and practical challenges remain. This seminar will present some of our recent experimental and theoretical progress regarding the mechanism of nonnative aggregation, the morphology, structure, and stabilizing forces for afibrillar aggregates, and improved mathematical models for predicting aggregation kinetics and mechanistically interpreting experimental data. The resulting models incorporate inputs from both experiment and coarse-grained statistical mechanical theory bridging molecular and macroscopic length scales, and also provide guidance for designing experiments to better predict and control aggregation kinetics, characteristics of the resulting aggregates, and the effects of seeding.