Co-Advisors
Stephen C. Harvey, Ph.D. (Georgia Tech)
Nael A. McCarty, Ph.D. (Emory University)

Committee
Cheng Zhu, Ph.D. (Georgia Tech)
Peter J. Ludovice, Ph.D. (Georgia Tech)
King Jordan, Ph.D. (Georgia Tech)

The CFTR chloride channel mediates salt and water movement across epithelia. Mutations in the gene encoding CFTR and the resulting dysfunction in the protein cause cystic fibrosis, the most common life-shortening disease among Caucasians. The long-term goal of our research is to identify the conformational changes in the CFTR channel pore that underlie the transitions between conducting and non-conducting states, and to identify the conduction pathway of the open state. CFTR is a member of the ABC transporter superfamily,  but it is the only member known to exhibit ion channel activity. Transporters generally function by means of an "alternating access" cycle in which the substrate binding site is alternately exposed to the inside or the outside of the cell through conformational changes in the protein,  without there ever being a continuous path from one side to the other. In CFTR, however, a continuous pore allowing anion conduction must exist, and conformational changes are thought to gate the pore open and closed. The structural basis for this fundamental difference is unknown. Using homology modeling and molecular dynamics simulations, we have identified possible structures for the open and closed states of CFTR and conformational transition pathways between them. We have also used our simulations to predict novel side chain interactions that are involved in stabilizing particular channel states, which have been confirmed experimentally. 

In this proposal, we will refine our homology modeling and molecular dynamics simulations through the use of a template that bears even closer resemblance to the purported CFTR structure. We will test the hypothesis that channel activity evolved in CFTR by converting the conformational changes associated with alternating access transport — as found in other ABC transporters — into the formation of a stable open state. We will identify sites where interactions between residues either hinder channel opening or promote the stabilization of the open states. In addition, we will use molecular dynamics simulations to study ion conduction in the open channel pore.