In the present work, we proposed to use a new protein–protein
docking approach to construct the human CFTR’s NBD1–NBD2
heterodimeric complex based on the crystal structure of human
CFTR’s NBD1 and a modeled structure of human CFTR’s NBD2 built
by using NBD1 as a mold. The method requires no a priori
knowledge of any dimeric structure of homologous proteins. It also
overcomes the potential severe backbone clashing problem in the
conventional overlying method. The constructed NBD1–NBD2
model was consistent with the experimentally observed NBD
dimers of ABC transporters (see[16]for review). To further validate
our model, we docked ATP molecules to the CFTR’s NBD1–NBD2
dimer, and reproduced the observed ATP binding mode in the
NBD1 monomer. Lastly, we used the modeled NBD heterodimer to
investigate the interaction between genistein and human CFTR’s
NBD dimer by molecular docking. Genistein is an isoflavonoid
found in soybeans and soy products that has a prominent effect in
potentiating CFTR channel activity[17–24]. It is regarded as the
gold standard for drug screening programs spearheaded by the
Cystic Fibrosis Foundation. However, the molecular mechanism of
genistein’s activation remains unclear. Based on our computational
results, the putative binding sites of genistein on CFTR were
identified, showing consistency with experimental findings