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Introduction

We are part of the Department of Structural Biology and Chemistry in Institut Pasteur, Paris.
Our field is Structural Biology and Molecular Biophysics.

We use biophysical experimental techniques such as crystallography and cryo-electron microscopy to visualize at the atomic level the structure of molecules essential to life, especially
- DNA polymerases involved in DNA Repair and Cancer
- Ion channels involved in electric nerve signaling (cell-cell communications).

We complement them with computational approaches such as molecular dynamics (atomic models), normal modes dynamics (coarse-grained models) and statistical thermodynamics, in order to go beyond the essentially static pictures given by these methods.
We also try to better understand the electrostatics properties of macromolecules and their interaction with the solvent and ligands, in order to be able to predict their binding properties.
Homology modelling and molecular phylogeny techniques are routinely used to enlarge our approach.

Our main goal is to understand how these molecular machines work at the atomic level so as to design structure-inspired drugs (pharmacology) and re-design their active site(s) to make them accept other substrates (synthetic biology).

Publications by year (2009-2019)

2020

-New article on the cryo-EM structure of archaeal polD + DNA + PCNA by Madru et al. (Nature Commun.) in Bioarxiv.

2019

-With main authors Patrice Koehl (UC Davis) and Henri Orland (CEA, Saclay), a new look at Optimal Transport theory using the tools of statistical mechanics, just published in Physical Review Letters (PRL) and E (PRE).
See articles here, PRL.pdf and PRE.pdf. A pseudo-distance can now be defined between the different solutions.
We are working on applications in the field of structural bioinformatics as well as IA.

-A structural model for human Pol mu interacting with an NHEJ junction containing a DNA double-strand-break, based on crystal structures of a TdT chimera that recapitulates all properties of Pol mu, published in JBC, see Access the
recommendation on F1000Prime.
This is a collaboration with the group of M.R. Lieber (USA).

-Cryo-EM structure of the polD DNA polymerase (DP1+DP2) complex, with or without DNA, in PLoS Biol.

-An updated structure-based classification of all extant DNA polymerases (Here).

-An exploration of multidimensional representation of amino-acids to retrieve structural information from very large sequence alignments (Here). See also a recent Review in F1000.

2018

-Molecular mechanism of proton gating in GLIC in PNAS and PDF.

-Fifth DNA Polymerases Meeting in Leiden, NL (Program here).

-CECAM Meeting on Normal Modes in IHP, Paris, September (Program here).

-New and faster calculations of Normal Modes with Patrice Koehl (Ref).

-Crystal structures of a new bacterial pentaLGIC at 2.3 Angstrom in a widely open form in PNAS and PDF.

-Positive and negative modulation of pentaLGICs by General Anesthetics in (Cell Rep. and F1000)

-Review on TdT in Current Opinion in Structural Biology (on line and F1000) and PDF.

-Design of a polymerase that generates libraries of random RNA in Nucleic Acids Res.

2017

-Simulating the transition path between two known forms of a macromolecule using mixed ENMs,
in J. Chem. Phys. This is a follow up of our previous MAP method (see also P. Koehl in J. Chem. Phys.)

-New methods in Normal Modes from Elastic Network Models (with Patrice Koehl) for automatic coarse-graining (JCTC) or dazzling speed (Front. Mol. Bios.)

-Organisation with Y.H. Sanejouand of a one day meeting in Normal Mode analysis and Conformational Transitions in Pasteur (30 May 2017)

-String method simulation of the transition pathway for GLIC, with Pr Toby W. Allen (Melbourne, Australia, corresp. author) in PNAS. See F1000

-X-ray structures of GLIC with Barbiturates, with Pr. Trevor Smart (UCL, UK) (J. Biol. Chem.) Editor's pick, Feb 3, 2017. See also here.

2016

DNA Polymerases and DNA Repair

-X-ray structure of Archaeal polD DNA polymerase reveals a catalytic site similar to multi-subunit RNA polymerases that are found in all domains of life, by L. Sauguet, P. Raia, G. Henneke and M. Delarue (Nature Commun). See F1000.

-Structural basis for an unexpected "in trans" templated activity by TdT: implications for V(D)J recombination and DNA double-strand-breaks repair in eukaryotes, J. Loc'h, S. Rosario and M. Delarue (Structure). See F1000.

Pentameric Ligand-gated ion channels (pentaLGICs): drug binding sites in different conformational states

-X-ray structures of GLIC with Xenon, in the open and locally-closed states, with N. Colloc'h (PLoS One).
-X-ray structures of GLIC with Bromoform with MD studies by M. Baaden and coll. (Structure).

2015

-TdT structures in complex with a DNA synapsis shed new light on DNA Double-Strand-Break Repair by NHEJ (EMBO J., Mar 2015).

-Structure of a GLIC-GlyR chimera with P.-J. Corringer (PNAS, Feb 2015)
-Structural characterization of allosteric binding sites in GLIC (Acta D, March 2015) see F1000

2014

-Structural basis for the gating mechanism in GLIC (PNAS, Jan 2014), see F1000
-A structural perspective in the pharmacology of pLGICs (BBA, May 2014)

2013

-Structural basis for ion permeation in GLIC (EMBO Journal, Jan 2013) at 2.4 Angstrom
-Structural basis for alcohol potentiation in mutant of GLIC with R.J. Howard (Nature Comms, April 2013) see F1000

-Snapshots of Terminal deoxynucleotidyl transferase caught in action: dynamical aspects of the two-metal-ion mechanism (J. Gouge et al., J. Mol. Biol., Jul 2013)
-Structures of inhibitors of Tdt, with G. Maga (Milan) and R. di Santo (Roma), J. Med. Chem., Sep 2013.

2012

-Structure of Archaeal DNA polymerase (polB) from P. abyssi in editing mode by J. Gouge et al. (JMB)

-A review on cys-loop receptors with P.J. Corringer in Structure
-The locally-closed form for GLIC in 2012, see F1000

2011

-The structure of a complex of general anesthetics with GLIC in 2011, see F1000

2010

-1 micro-second long MD simulation of GLIC with Marc Baaden in 2010, see F1000

2009

-The structure of the open form of GLIC with P.J. Corringer in 2009, see F1000

-The AquaSol model was extended to include solvent-solvent interactions in PRL, see F1000

Software

The following web sites provide online servers for algorithms such as normal mode calculation, structural refinement, solvation, mutation and (later) transition path calculation.
The primary application is for biological macromolecules like proteins or DNA or complexes thereof.

AquaSAXS, a web-based software to calculate SAXS spectra from PDB coordinates, including the solvent density predicted by AquaSol, see Ref. here.
The underlying dipolar model for the solvent was described in Biophysical Journal (coll. H. Orland).
The web server AquaSol is the newest implementation of this dipolar solvent model, due to P. Koehl.

MinActionPath (MAP) web server can be used to generate the most probable trajectory between two known structural forms of the same macromolecule (see Ref. here). The algorithm was greatly accelerated by P. Koehl, as described here.

The NOMAD_Ref web server (see Ref. here) allows to calculate Normal Modes in the Elastic Network Model, and has some applications in X-ray refinement.

The PDB_Hydro web server (see Ref. here) has many features for modeling, in addition to electrostatic calculations (contained in AquaSol).

Go to Older web site for more details on the group activities before 2009.

NOMAD-Ref web server
Normal Mode Analysis
NOMAD-Ref web server
Normal Mode Refinement
PDB_Hydro web server
Mutation & Solvation: Dipolar solvent
PDB_Hydro web server
AquaSaxs web server




  Marc Delarue http://lorentz.dynstr.pasteur.fr