Molecular dynamics simulation study on the structural instability of the most common cystic fibrosis-associated mutant ΔF508-CFTR

Abstract

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that belongs to the ATP binding cassette protein superfamily. Deletion of phenyl-alanine at position 508 (ΔF508) is the most common CF-associated mutation and is present in nearly 90% of CF patients. Currently, atomistic level studies are insuf-ficient for understanding the mechanism by which the deletion of a single amino acid causes greatly reduced folding as well as trafficking and gating defects. To clar-ify this mechanism, we first constructed an atomic model of the inward-facing ΔF508-CFTR and performed all-atom molecular dynamics (MD) simulations of the protein in a membrane environment. All of the computational methodologies used are based on those developed in our previous study for wild-type CFTR. Two important findings were obtained. First, consistent with several previous computational results, the deletion of F508 causes a disruption of a hydrophobic cluster located at the interface between the nucleotide binding domain 1 (NBD1) and intracellular loop 4 (ICL4). This exerts unfavorable influences on the correlated motion between ICLs and transmembrane domains (TMDs), likely result-ing in gating defects. Second, the F508 deletion affected the NBD1–NBD2 interface via allosteric communication originating from the correlated motion between NBDs and ICLs. As a result, several unusual inter-residue interactions are caused at the NBD1–NBD2 interface. In other words, their correct dimerization is impaired. This study provided insight into the atomic-level details of structural and dynamics changes caused by the ΔF508 mutation and thus provides good insight for drug design.