Round Table Seminar: Jue Fan, Rhee Lab - Carnegie Institution - Plant Department, Identification of Folding Pathways of BBL by Probabilistic Network Analysis.

In this seminar, I will present one of my Ph.D. projects. Protein folding is an old yet unsolved problem, the understanding of which is essential in the research areas such as protein engineering and drug design. BBL is an independent folding domain from the E2 subunit of a large multienzyme complex of E. coli, 2-oxoglutarate dehydrogenase. The folding mechanism of BBL is experimentally under debate between the views of downhill-type and classical two-state. In this work, we used a two-step strategy to tackle the question in silico: replica exchange molecular dynamics to enhance sampling of protein conformational space and the probabilistic network to locate the optimal pathways from extended state to native state. Our method revealed atomically detailed folding pathways. Two distinct clusters of folding pathways were found. One path shows that tertiary contact and helix formation develop at different stages of folding, whereas the other path exhibits concurrence of secondary and tertiary structure formation to some extent. We speculate that the relative predominance of the two pathways may vary with the protein construct and solvent conditions, possibly leading to the seeming discrepancy of experimental results.