Group of Marc Delarue
Unit of Structural Dynamics of Macromolecules


puce Overview: experimental and computational structural molecular biology

We use experimental techniques such as x-ray crystallography, cryo-EM and SAXS to visualize at the atomic level the structures and conformational states of molecules essential to life such as DNA polymerases or ion channels.
We complement them with normal modes analysis and (targeted) Langevin dynamics, so as to go beyond the static pictures given by these methods and describe on a coarse-grained level the pathway of orthosteric or allosteric transitions between functional states.
Evolutionary data (sequence alignments) must also be used to uncover what has been conserved throughout evolution.
In this way we study the tryptich "Structure-Dynamics-Sequences" or "Architecture-Fluctuations-Evolution" in order to understand functional properties of biological macromolecules.

We also try to better understand the electrostatics of macromolecules and their interaction with the solvent, in order to be able to predict their binding properties with other molecules (proteins, substrates, allosteric modulators).
Our main goal is to design structure-inspired drugs (pharmacology) and re-design active site(s) to make them accept other substrates (synthetic biology).

We study experimentally the structural and dynamical properties of the following biological molecular machines

puce  DNA polymerases (esp. polX) involved in DNA repair, immunology and cancer (Pol1, Pol2).
puce   Eukaryotes: A single mutation transforms Tdt (V(D)J) into a template-dependent pol mu (NHEJ).
puce  DNA polymerases involved in the replication of Archaea
puce   Archaea: structural basis for the evolution of DNA replication apparatus in archaea polD.
puce  Pentameric ligand-gated ion-channels
puce   Bacteria: allosteric transitions in the pH-activated ion channel from the cyanobacterium Gloeobacter violaceus (GLIC)

puce  We also work with chemists to design new structure-inspired drugs against protein targets from pathogens.

We develop new computational methods to predict thermodynamical and dynamical properties of macromolecules.

puce   Electrostatics with free ions and a dipolar solvent model with P. Koehl (UC Davis) and H. Orland (CEA)
puce   Coarse-grained dynamics and Normal Modes using the Elastic Network Model (ENM - see Y.H. Sanejouand).
puce   Generating plausible pathways between two known end-points of an (allosteric) structural transition (coll. H. Orland).
Crystals (left) and structure (right) of a bacterial homologue of the nicotinic acetylcholine receptor (GLIC)

puce Striking Results

puce  Crystal structure of Tdt, first structure of an eukaryotic polX in EMBO J., 2002
puce  How to transform Tdt into pol mu by single-point mutations in NAR, 2009
puce  Snapshots of Tdt structural changes during the catalytic cycle by Jerome Gouge et al., JMB, 2013
puce  Structural basis for DNA bridging and alignment by Tdt in V(D)J recombination by Gouge et al., EMBO J, 2015
puce  Structural basis for in trans templated DNA synthesis by Tdt, by J. Loc'h et al., Structure J, 2016
puce  New structures of an archaeal polB DNA polymerase by Jerome Gouge et al., JMB, 2012
puce  New structures of an archaeal polD DNA polymerase by L. Sauguet et al., Nature Comms, 2016

puce   Structural studies of the pentameric cys-loop ion channel family with P-J Corringer: see press release CNRS
puce   X-Ray structure (2009) of a bacterial analogue of the acetylcholine receptor (GLIC), in Nature
puce   X-Ray structure (2011) of the complex between GLIC and two anaesthetics, in Nature
puce   X-Ray structure (2012) of a new "locally-closed" structure of GLIC, in NSMB
puce   A recent review on cys-loop nicotinic receptors, in Structure, 2012
puce   Structural basis of ion permeation in GLIC, EMBO J., Jan 2013
puce   Structural basis for alcohol potentiation on an ethanol-sensitized GLIC mutant, Nature Comm., April 2013
puce   Structural basis for gating by protons in GLIC, PNAS, January 2014

puce  Macromolecular electrostatics with a dipolar solvent model (2008), (2009a), (2009b), (2010) and (2011).
puce  One more recent application of this model (AquaSol) is described in Biophys. J. (2013)

puce Web services
puce  NOMAD-Ref for Normal Modes applications (including positional refinement against X-Ray and cryo-EM data)
puce  PDB_hydro (now AquaSol) for modelling mutants and get electrostatics properties with the dipolar solvent model
puce  MinActionPath for generating the most probable path between two known structural forms.
  N.B. The MinActionPath project has been sponsored by Apple's ARTS program (2007).
puce  AquaSAXS, to calculate SAXS spectra from PDB coordinates and the solvent density predicted by AquaSol

puce Presentation
puce  Members
puce  Research
puce  Publications


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