Computational analysis of long-range allosteric communications in CFTR

Abstract Malfunction of the CFTR protein results in cystic fibrosis, one of the most common hereditary diseases. CFTR functions as an anion channel, the gating of which is controlled by long-range allosteric communications. Allostery also has direct bearings on CF treatment: CFTR drugs bind at the periphery of the protein yet affect the gating residues that lie at the center of it. Herein, we combined two computational approaches; Anisotropic Normal Mode-Langevin dynamics (ANM-LD) and Transfer Entropy (TE) and investigated the allosteric communications network of CFTR. The results are in excellent agreement with experimental observations and provide extensive novel insight. We identified residues that serve as pivotal allosteric sources and transducers, many of which correspond to disease causing mutations. We observe that the degenerate and catalytic ATP sites asymmetrically contribute to the allosteric communication, and that the catalytic site provides the greater allosteric input. We demonstrate that drugs that potentiate CFTR’s conductance do so not by directly acting on the gating residues, but rather by mimicking the allosteric signal sent by the ATP binding sites. We identify a hitherto unknown allosteric hotspot near the docking site of the phosphorylated R domain, providing a molecular basis for its phosphorylation dependent excitatory role. This study uncovers the molecular basis of allosteric connectivity in CFTR and reveals a novel allosteric hotspot that can serve as a target for the development of novel therapeutics.