Cystic fibrosis (CF) is a frequent genetic disease in Caucasians that is caused by
the deletion of F508 (DF508) in the nucleotide binding domain 1 (NBD1) of the CF transmembrane
conductance regulator (CFTR). The DF508 compromises the folding energetics of the
NBD1, as well as the folding of three other CFTR domains. Combination of FDA approved
corrector molecules can efficiently but incompletely rescue the DF508-CFTR folding
and stability defect. Thus, new pharmacophores that would reinstate the wildtype-like
conformational stability of the DF508-NBD1 would be highly beneficial. The most prominent
molecule, 5-bromoindole-3-acetic acid (BIA) that can thermally stabilize the NBD1
has low potency and efficacy. To gain insights into the NBD1 (un)folding dynamics
and BIA binding site localization, we combined molecular dynamics (MD) simulations,
atomic force spectroscopy (AFM) and hydrogendeuterium exchange (HDX) experiments.
We found that the NBD1 a-subdomain with three adjacent strands from the b-subdomain
plays an important role in early folding steps, when crucial non-native interactions
are formed via residue F508. Our AFM and HDX experiments showed that BIA associates
with this a-core region and increases the resistance of the DF508-NBD1 against mechanical
unfolding, a phenomenon that could be exploited in future developments of folding
correctors. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Research
Network of Computational and Structural Biotechnology. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
