Keynote Lecture
Computational Studies of CFTR, an Ion Channel Implicated in Cystic Fibrosis

Cystic Fibrosis (CF) is a lethal, incurable genetic disease with a median lifespan in the late thirties. Currently, the worldwide number of CF patients is estimated at 70,000 with about 600 in Israel. CF is caused by mutations to the CFTR chloride channel, a member of the ABC transporters family. Over 2000 mutations of CFTR were reported with different prevalence and mechanisms of action. All mutations compromise the ability of the channel to transport chloride ions across cell membranes thereby disrupting the ion-liquid balance across the epithelial cells lining the respiratory system. This leads to dehydration of the mucus layer lining the lungs and to its colonization by bacteria, ultimately resulting in chronic lung disease and lung failure.

Developing effective therapies for CF would be greatly advanced by high resolution structural, functional and energetic characterization of full length CFTR and its domains and by the understanding of the effects of clinical mutations as well as drug interactions.

With this in mind, we present a series of computational studies demonstrating the ability of molecular modeling tools to probe the structure, dynamics, and drugability of CFTR and its domains [1-3]. We will also present new CFTR models generated by using Molecular Dynamics Flexible Fitting simulations. These models take advantage of recent developments in Cryo electron microscopy (EM) leading to EM maps of increasingly higher resolutions. Lessons learnt from CFTR may be transferable to other ABC transporters implicated in diseases.

1. Zhenin et al., Chem. Inf. Model., 2015, 55, 2349–2364.
2. Hudson, et al., J Biol Chem. 2012, 287, 28480-94.
3. Noy et al., ChemMedChem 2011, 6, 243-51.