Modeling the Conformational Changes Underlying Channel Opening in CFTR
Figure 5
Tracking the conformational changes in CFTR channel opening by following particular side-chain interactions.
A shows close-ups of the R352-D993 salt bridge [30] and the R555-T1246 inter-NBD hydrogen bond [16], which exist only in the open state, and the proposed novel R258-E282 and R334-E217 salt bridges which exist only in the closed state. Tracking the formation and breaking of these interactions over the course of the simulation (B) shows that the NBDs form a stable dimer at around 4 ns. The conformational wave then proceeds upwards through the ICLs, where the R258-E282 salt bridge is broken at ∼6 ns, and then to the transmembrane region where the R352-D993 salt bridge is formed nearly 7 ns after the beginning of the simulation. The point at which the R334-E217 salt bridge that stabilizes the closed state breaks is also indicated (∼6.3 ns). Distances between residues in part (B) are measured between interacting side chain heavy atoms, specifically the guanidinium N of arginines, carboxyl O of E282 and D993, and hydroxyl O of T1246.