We are part of the Department of Structural Biology and Chemistry in Institut Pasteur, Paris.
Our main field is Structural Molecular Biology augmented by techniques of Computational Biology,
venturing into topics of Synthetic Biology.
We use experimental techniques such as crystallography and cryo-electron microscopy to visualize at the atomic level
the structure of molecules essential to life and to understand their functional properties, especially for:
• DNA and RNA polymerases involved in genome replication and other transactions (repair, transcription, transposition...)
• Ion channels involved in electric nerve signaling and cell-cell communications.
We complement them with computational approaches such as molecular dynamics (atomic models),
normal modes dynamics (coarse-grained models), conditioned Langevin dynamics
in order to go beyond the essentially static pictures given by these methods.
In addition, (ensemble) statistical thermodynamics
allow us to make use of the all the information contained in
biodiversity. The massive sequence data of related molecules in the tree of life can help to understand
what is essential in their active site structure and how it is modulated (allostery).
Our main goal is to understand how these molecular machines interact with partners at the atomic level, their solvation and binding properties (including electrostatics),
so as to design structure-inspired drugs (pharmacology and drug discovery).
When possible we study their structure in the context of their partners in larger
macromolecular complexes in order to mimic their behaviour in cellulo
and to understand their regulation as well as possible emerging collective properties (systems biology).
Protein engineering: Another aim is to make enzymes evolve by directed evolution techniques and get inspiration in the design of new biological functions
using biodiversity and especially phage genomes (synthetic biology).
We study the molecular mechanism of DNA Repair for Double Strand Breaks by the Non-Homologous End Joining (NHEJ) process in eukaryotes using x-ray crystallography and cryo-EM, especially steps involving pol mu or TdT
We work with archaeal (PolB) and bacterial thermophilic (polA) DNA polymerases to change their specificity by directed evolution techniques, using structural information to guide the design of libraries.
We study the general architecture of the replisome in archaea, especially around the essential PolD, that we discovered to be unique among other DNA polymerases, as it has the fold of multi-subunit RNA polymerases.
We are developing new computational methods to calculate the electrostatics of proteins, understand their dynamical properties and simulate transitions between two known conformations of the same macromolecule.
We study the structure and function of ligand-gated ion channels by X-ray crystallography to understand
• the gating mechanism (opening of the pore upon agonist binding)
• the permeation mechanism (transport of ions through the pore)
• modulation by allosteric compounds (general anesthetics, barbiturates…)