Société Française de Bioinformatique

Mots-Clés

molecular dynamics membrane proteins cystic fibrosis

Description

Molecular dynamics study of the modulation mechanisms of the CFTR channel (cystic fibrosis)
The CFTR (cystic fibrosis transmembrane conductance regulator) protein, which belongs to the ABC transporter superfamily, is an anion channel whose mutations cause cystic fibrosis (CF). Despite the availability of experimental structures capturing CFTR in several conformational states, including structures in complex with pharmacological modulators currently used to treat patients with CF, the molecular mechanisms leading to its opening and modulation are not yet fully understood.
This M2 project aims to decipher the molecular mechanisms governing CFTR channel opening, both in the absence and in the presence of modulators, and to investigate the impact of CF-causing mutations and their responsiveness to modulators. The ultimate goal of these studies is to develop new modulation strategies for CF-causing mutations that respond poorly or remain resistant to current treatments.
Molecular dynamics simulations will be performed using 3D structures of wild-type and mutated CFTR embedded in an heterogeneous and asymmetric bilayer of lipids, consistent with the composition of epithelial membrane. The resulting trajectories will be analyzed using structural and dynamic descriptors, such as electrostatic bonds and transmembrane irregularities building on the approaches described in Elbahnsi et al. (2026) for simulations of wild-type CFTR. Comparative analyses will be conducted to identify molecular signatures associated with channel modulation, characterize ion entrance and exit pathways, and identify potential ligand-binding pockets that could represent new sites for pharmacological modulation.

This M2 internship will be co-supervised by Dr Ahmad Elbahnsi (CR CNRS, CiTCoM, Université Paris Cité) and Dr Isabelle Callebaut (DR CNRS, IMPMC, Sorbonne Université), who are both expert in the structural bioinformatics of CFTR and membrane transporters. This project is supported by the association Vaincre La Mucoviscidose and by high-performance computing resources provided by the CINES.

The candidate should demonstrate experience with the Linux environment and the methods used in structural biology, molecular modeling, and molecular dynamics. He/she must demonstrate curiosity and a genuine ability to organize his/her work independently within a research environment.

Relevant publication
Elbahnsi A, Mornon JP, Callebaut I. Mechanistic Insights into Cystic Fibrosis Transmembrane Conductance Regulator Function from Molecular Dynamics Analysis of Electrostatic Interactions. J Chem Inf Model. 2026 May 25;66(10):5990-6010. doi: 10.1021/acs.jcim.5c02661, HAL-Id : 05691876.