ATP-Binding Cassette (ABC) proteins are large transmembrane efflux transporters that hydrolyze ATP to export substrates against the concentration gradient. They belong to a protein super-family composed of 7 different sub-families (A-G) that play essential roles in drug transport, metabolism and pharmacokinetics. Due to their efflux capabilities, they are crucial in protecting cells from xenobiotics, harmful compounds and metabolites.

Aside from those involved in multidrug resistance (MDR) in cancer, ABC proteins can also lead to other forms of illness through point mutations that can cause protein misfolding and misbehavior. The Cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7) is a member of this transporter family, being directly responsible for causing cystic fibrosis (CF), the most common life-shortening rare disease.

According to the European Cystic Fibrosis Society Patient Registry, there were 54,546 registered people with CF across 39 European countries in 2022. The F508del mutation in the CFTR protein occurs in 85% of CF patients and leads to protein misfolding, negatively impacting protein activity and causing an ion gating defect. Despite emerging therapeutic options, patients quality of life is still limited and the therapies are not effective in all mutations.

Small molecules capable of correcting this condition are greatly sought after. Furthermore, the CFTR R domain, is still challenging to model due to its large size, unstructured nature and high conformation mobility. Herewith, we report on a refined and functional model of CFTR using in silico methods, aiming at further understanding anion permeation and the impact of different mutations on the gating mechanism.