Cystic fibrosis transmembrane conductance regulator (CFTR) is a member of the ATP-binding
cassette (ABC) transporter superfamily that has uniquely evolved to function as a
chloride channel. It binds and hydrolyzes ATP at its nucleotide binding domains to
form a pore providing a diffusive pathway within its transmembrane domains. CFTR is
the only known protein from the ABC superfamily with channel activity, and its dysfunction
causes the disease cystic fibrosis. While much is known about the functional aspects
of CFTR, significant gaps remain, such as the structure-function relationship underlying
signaling of ATP binding. In the present work, we refined an existing homology model
using an intermediate-resolution (9 angstrom) published cryo-electron microscopy map.
The newly derived models have been simulated in equilibrium molecular dynamics simulations
for a total of 2.5 mu s in multiple ATP-occupancy states. Putative conformational
movements connecting ATP binding with pore formation are elucidated and quantified.
Additionally, new interdomain interactions between E543, K968, and K1292 have been
identified and confirmed experimentally; these interactions may be relevant for signaling
ATP binding and hydrolysis to the transmembrane domains and induction of pore opening.