TITLE: "Computer Simulation Studies of Protein Folding and Aggregation"

SPEAKER: Professor Carol K. Hall,

To recover active protein from the denatured protein aggregates (inclusion bodies) often formed during recombinant synthesis of proteins, it is often necessary to first dissolve the protein in a strong denaturant and then refold the resulting de-aggregated protein via multiple dilution steps or dialysis. A major problem that arises, however, is that as the denaturant is removed, partially refolded intermediates of the proteins can themselves re-aggregate, preventing progression towards the native state and resulting in low yields of active protein. In an attempt to gain insights that might eventually lead to the development of new ways to avoid or minimize loses due to aggregation, we have performed dynamic Monte Carlo simulations on model systems containing both isolated and multiple protein chains. Proteins were modeled as a chain of hydrophobic and polar beads arranged in a unique sequence on a two-dimensional square lattice. Protein folding pathways, intermediate populations, protein refolding yields and aggregation were monitored as a function of both denaturant concentrations and protein concentration. We find that there exists an optimum level of denaturant and protein concentrations at which the refolding yield is highest, in agreement with experimental observations. We also find that the stability of the various types of protein intermediates is governed by a set of often conflicting molecular mechanisms; the winner of this competition depends on both protein and denaturant concentrations.