P-glycoprotein (P-gp) is one of the most studied ABC transporters which plays a key role in the ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) properties of very diverse xenobiotics and drugs. Moreover, P-gp is of major interest in cancer treatment because of its involvement in the multidrug resistance (MDR) phenotype by expelling anticancer drugs out of tumor cells, thus reducing their therapeutic activity. The inhibition of P-gp also causes drug-drug interactions (DDI) which have an impact on drug efficacy/toxicity. The ability to identify substrates and inhibitors of P-gp is therefore crucial to prevent DDI and adverse drug reactions (ADR) during the clinical stages of the drug development process. 

I am using standard molecular dynamics (MD) and enhanced sampling methods to generate transient conformations during the conformational cycle of P-gp. This research aims to uncover the mechanisms of substrate efflux and inhibitor interactions. The simulation data has provided insights into the transition pathway of P-gp, revealing important functional and dynamic features. These findings are valuable for: i) refining the definition of binding sites, ii) characterizing their interactions with known active compounds, and iii) facilitating the prediction of new inhibitors and substrates.

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The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein is a particular member of the ABC transporter family. In fact, it is the only known member of this family that functions as an anion channel, mediating the transport of chloride and bicarbonate across the apical membranes of epithelial cells. As CFTR mutations lead to the inherited disease Cystic Fibrosis, it represents an important target for drug discovery, with challenging issues related to the development of modulators specific for each class of mutations.

The main aim of my work is to provide a better sampling of CFTR conformational transitions that are taking place between the different states of the channel and evaluate impacts of mutations and/or modulators (after searching of their binding sites).

This work is conducted in close collaboration with chemists (University of Grenoble Alpes, University of Paris Descartes) and biologists (Necker Institute, University of Poitiers, University of Bretagne) 

My project was funded and supported by the French cystic fibrosis foundation (Association Vaincre La Mucoviscidose).

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ABCB4, also called MDR3, is a member of the MultiDrug Resistance (MDR) transporter family, which deficiency causes Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3), a severe rare biliary disease that represents a major challenge for the European Community. ABCB4 flops membrane phospholipids from the inner leaflet to the outer leaflet of the hepatocyte canalicular membrane. Failure to flop enough PC results in the formation of cytotoxic bile, leading to cellular damage, inflammation and cholestasis.

This project aims to understand how ABCB4 facilitates PC binding and translocation through extensive molecular dynamics simulations based on cryo-EM structures and full-length ABCB4 models. The study also investigates the impact of ABCB4 mutations similar to CF gating mutations and suggests potential rescue of PC secretion defects using CFTR potentiators, supported by experimental evidence. These findings suggest that the same drug could be effective for multiple ABC transporters with similar variations.

The functional validation is performed by experimental collaborators at CDR Saint-Antoine - Sorbonne University, Paris.

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Ferroportin 1 (FPN1) is the only known iron exporter in mammals. Dysfunction causes hemochromatosis type 4A (or ferroportin disease), which is the commonest cause of inherited iron overload after HFE-related hemochromatosis. Despite its fundamental role in iron metabolism, the molecular mechanisms underlying the FPN1 export cycle are still elusive. 

This work is conducted in collaboration with experimental researchers from University Bretagne Loire – University of Brest.

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The nucleosome is the fundamental unit of DNA compaction in eukaryotic cells. It consists in a long DNA segment (145-147 bp) wrapped in 1.7 left-handed superhelix turns around a histone octamer. Nucleosomes control the DNA accessibility by assembling and disassembling along the genomes and are therefore involved in most nuclear processes.

The main aim of my thesis was to describe the DNA-histone interface in solution to better understand the nucleosome stability. We examined in particular how the DNA is maintained wrapped around the histone and how its sequence affects the DNA-histone interface. Several nucleosomes were studied using molecular dynamics in explicit solvent ; they differed by the tail length and the DNA sequences. To ensure an objective analysis of the topology of the DNA-histone interface, a method based on Delaunay-Laguerre tessellations, originally developed for proteins, was adapted to nucleic acids.

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