CFTR and cystic fibrosis: On the other hand, considering that the most common cystic fibrosis mutation F508del damages CFTR folding by destabilizing NBD1 or its interactions with ICL4, leading to a failure of Mg/ATP-dependent NBD dimerization for normal channel gating (13–28), the systematic fluidic grid-like noncovalent interaction mesh networks of NBD1, with or without the interactions with ICL4, have been constrained as thermoring structures with the minimum energy required to stabilize the interactions (29–30).