Mots-Clés

bioinformatics, computational chemistry, molecular modelling software, protein-RNA complex, methylation, MD simulations

Description

Context

The internship will be conducted in the MMVRT (Molecular Mechanisms of viral RNA translation) team of CiTCoM (UMR CNRS 8038, Université Paris Cité UPC), a multidisciplinary unit with expertise in molecular modelling, biochemistry, organic chemistry, structural biology, and microbiology.

The position is part of the two-year project MADESAM (MultiScale Modeling And Designing of SAM Analogues for RNA Methylation Inhibition) funded by University Paris Cité in the context of the action Idex Emergence. The co-PI of the project, Prof. Mélanie Etheve-Quelquejeu (LCBPT, UPC), is an expert in organic chemistry, in particular in nucleoside and nucleotide chemistry applied to the modification of RNA. She has developed efficient synthetic routes to obtain stable analogues of aminoacyl-tRNA or bisubstrate analogues of methyltransferases enzymes. MADESAM aims to combine the complementary expertise of the two teams to provide a unique interdisciplinary approach for the study and modeling of the methylation inhibition of the RNA methyltransferases (MTases) METTL16 for the nucleotide modification N6-methyladenosine (m6A) to design new specific analogues for this enzyme. It is important to point out that m6A RNA MTases are notably involved in cancer progression as well as viral infection and are thus promising drug targets. The project is also conducted in close collaboration with our experimental colleagues in the team to validate our predictions who are expert in biochemistry and biology.

Position and assignments

The M2 internship is related to the study of the dynamics and flexibility of METTL16 to understand its activation and inhibition mechanism. Specific small molecules designed by the experimental collaborators involved in the project will be considered. The research project aims to develop new specific ligands that selectively inhibit METTL16. To do so, docking calculations and standard and advanced all-atom MD simulations will be performed. To study the reactivity, preliminary QM/MM calculations will be conducted. Statistical and bioinformatics analyses will be performed by using standard tools and by developing new scripts.

The M2 internship should be considered as an initiation into theoretical and computational methods spanning from simple QM calculations to standard and advanced all-atom molecular dynamics simulations using a variety of molecular modelling software and visualisation tools. Moreover, the intern will have the opportunity to learn about bash script coding, python, Matlab, High Performance Computing and to perform bibliographic research.

The internship will start at the beginning of the second semester of 2024/2025 M2 courses (January/February 2025).