Trikafta restores thermodynamic coupling between two nucleotide binding domains for potentiating CFTR activity

Trikafta modulators can correct the folding, thermal and gating defects of the most common cystic fibrosis mutant F508del of the human cystic fibrosis transmembrane conductance regulator. While folding correctors VX-445 and VX-809 are sufficient to rescue its folding and thermal defects by restoring Mg/ATP mediated dimerization between the two nucleotide binding domains (NBD1 and NBD2), the thermodynamic basis for the precise activity potentiation by VX-770 in Trikafta remains unknown. In this computational study, the thermoring structures and interdomain interactions of NBD2 were examined and compared with the counterparts of NBD1 with or without F508 in response to ligand and modulator binding. The results demonstrated that comparable thermostability between dimerized NBD1 and NBD2 was required to stabilize an activated intermediate for the channel activity potentiation by VX-770. Thus, tight coupling between dimerized NBD1 and NBD2 upon a global induced fit across the interdomain interfaces is still required for Trikafta modulators to rescue the gating defect of the F508del mutant.