(281a) Dynamics of Protein Aggregation — Crowding Effect in Confined Environment

Protein aggregation is associated with a variety of human neurodegenerative diseases, including Alzheimer’s, Parkinson’s and prion disease. The aggregates’ structural characteristics and molecular-level details are, however, difficult to study experimentally and, thus, the mechanisms of aggregation still remain poorly understood. Advances in computational power and molecular/atomistic simulation techniques, particularly, molecular dynamics (MD) simulations, provides the opportunity to simulate the aggregation process, hence helping us to unveil the secrets behind the phenomena and contributing to the development of therapeutic schemes for these diseases.

Most of the current MD studies about protein aggregation are conducted in bulk solution with focus on protein folding and unfolding. However, the cellular environment in which proteins aggregate is heterogeneous and often highly crowded. The effects arising from excluded volume interactions either due to macromolecular crowding, or localization of the protein in a small volume, or the extra interactions of protein and the confining boundary can have significant effects on protein aggregation.

We investigate the aggregation of multiple peptides in confined environments. The size of the peptides ranges from 10 to 30 amino acids. Two types of confined environments (cylindrical and spherical pores) are examined. The simulation method adopted is Discontinuous Molecular Dynamics (DMD) due to the long-time scale of aggregation of large molecules. The simulations reveal various types of fibril aggregates whose structures are also reported in experimental studies. Various properties of the aggregates have been calculated, including aggregation dynamics, size distribution of aggregates and β-sheet formation. The effects of confinement and types of confinement on the dynamics of aggregation are also studied and compared. We show that the aggregation process follows dynamic scaling that colloidal aggregates follow in unbounded media. To our knowledge, this is the first time that a full process of multi-peptide aggregation in confined environment is performed and studied. It is also the first time that the dynamic scaling that the aggregation process follows has been reported.