Conformational Dynamics of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Revealed by Molecular Simulations

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that supports functions of secretory organs. Dysfunctional CFTR in humans causes Cystic Fibrosis (CF), a lethal disease that results in the failure of lungs and various secretory glands. Phosphorylation and ATP-binding were shown to lead to the opening of the gate in CFTR; however, several recent near-atomistic cryo-EM structures of phosphorylated, ATP-bound CFTR remain in an apparently closed state, as suggested by the presence of a constriction at the extracellular end of the channel. We hypothesize that the cryo-EM structure of CFTR may relax to a functionally open state when placed in a lipid bilayer. To test this hypothesis, we performed repeated microsecond-long atomistic molecular dynamics (MD) simulations on the ATP-bound structures of CFTR in explicit pure POPC and POPS bilayers. In 2 out of 40 MD time trajectories, structural relaxation in the transmembrane domains of the channel leads to putatively open or pre-open states characterized by the presence of continuous pathways of hydrogen-bonded water molecules. Specifically, local conformational transitions involving changes in helical bend correlate with the formation of continuous water pathways. Potential of mean force calculations for chloride translocation through the channel are currently underway to validate the putatively open or pre-open configurations of CFTR obtained from simulations.