Société Française de Bioinformatique

Mots-Clés

bioinformatics computational chemistry molecular modelling software RNA modifications tRNA QM/MM methylation flavin dUMP

Description

Context
The internship will be conducted in the STAV (Structure and Translation of Viral RNAs) 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. One of the team research axes is dedicated to RNA functional modifications from experimental to computational point of view. An example is provided by flavin/folate-dependent methyltransferases such as TrmFO (m⁵U54 modification in tRNAs) and ThyX (synthesis of dTMP from dUMP) that catalyse reductive methylations essential to bacterial biology. These enzymes, which are absent in humans in the case of ThyX, are promising therapeutic targets against resistant pathogens. Unlike classical mechanisms via SAM, these enzymes use a flavin-dependent pathway, in which reduced FAD receives a methylene group from CH₂THF, activated by a redox step involving NADPH, and then transfers this group to the target. Two novel species have recently been proposed as key intermediates: FAD=CH₂ (flavin iminium) in TrmFO and FAD–CH₂OH (carbinolamine) in ThyX. The project will be conducted in close collaboration with the group of our collaborators headed by Dr. Djemel Hamdane at Sorbonne Université ) who has provided structural and spectroscopic evidence for these intermediate states (Angew. Chem. Int. Ed. 2017; Nat. Commun. 2021), but the mechanistic details of CH₂ group transfers and substrate activation remain to be elucidated.
Position and assignments
The M2 internship aims to decipher the enzymatic mechanisms of these two flavoenzymes using molecular modelling approaches. The goal is to identify the key transition states in the transfer of the methylene group from CH₂THF to flavin, then from flavin to the substrate (dUMP or tRNA). All-atom and QM/MM calculations will be carried out. 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 2025/2026 M2 courses (January/February 2026). The intern will also have the possibility to apply to the doctoral school competition.