Mots-Clés

Protein Per- and polyfluoroalkylated substances (PFAS) Molecular Modeling Docking Molécular Dynamics

Description

SCIENTIFIC CONTEXT

Per- and polyfluoroalkylated substances (PFAS) are a family of artificial chemical compounds with a wide range of properties: non- stick, waterproofing, heat resistance, etc. There are several thousands of them on the market in various day-to-day products. Because of the high stability of the carbon-fluorine bond, they are the most persistent man-made pollutant known to date, and exposure to PFAS can lead to serious adverse health effects. Some specific interaction between PFAS and proteins have been described, and molecular modeling can help to decipher how some PFAS can be transported by proteins in the body (Delva-Wiley, J. 2021). The aim of this project, financed by the CNRS, is to model the molecular interactions between PFAS and the FABP family of proteins (Fatty Acid Binding Protein), to describe the pathways of PFAS in the body and their actions on human metabolism.

MISSIONS for the 5 to 6 months internship
After some bibliography work, the student is going to use different numerical modeling techniques to map the interaction and dynamics of the PFAS/FABP complex. The conformations of the protein FABP are described by molecular dynamics (MD) simulations. Common conformations are used to perform molecular docking, with an algorithm that finds probable conformations of the PFAS/FABP complex. The student will then perform molecular dynamics simulations of these PFAS/FABP complex and investigate their stability, find relevant molecular interactions. We shall focus on differences between different PFAS and try to understand which PFAS are interacting more strongly with the FABP. Finally, we wish to investigate the dynamics of dissociation, by using the τ-RAMD (for Random Accelerated Molecular Dynamics) method (Kokh, 2028 and 2020). This accelerated method, implemented in the GROMACS software, will enable us to compare complexes according to their dissociation times.

The student will also interact with the two other teams that participate to the project, from the "Laboratoire des Biomolecules", in Paris, and from the laboratory "Matrice Extracellulaire et Dynamique Cellulaire" in Reims.

SKILLS
We are looking for a Master 2 student in chemistry, physics, bioinformatics, computational biology, or equivalent, with the following skills:
- Python programming
- Scientific English

The following skills will be a plus:

- Knowledge of biochemistry of proteins

- Basic knowledge of statistical physics

- Experiences with molecular dynamics simulation or docking

OUTLOOKS
The project may be continued as a phD thesis provided that a doctoral school grant is obtained.

BIBLIOGRAPHY
- Delva-Wiley, J. et al. (2021). Computational Analysis of the Binding Mechanism of GenX and HSA. ACS Omega. 6, 43, 29166–29170, https://doi.org/10.1021/acsomega.1c04592
- Kokh, D. et al. (2018). Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations. J. Chem. Theory Comput., 14, 7, 3859–3869 https://pubs.acs.org/doi/full/10.1021/acs.jctc.8b00230
- Kokh, D. (2020). tauRAMD. github repository https://github.com/HITS-MCM/tauRAMD