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Introduction

We are part of the Department of Structural Biology and Chemistry in Institut Pasteur, Paris.
Our main field is Structural Molecular Biology and Biophysics augmented by some techniques of Computational 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 or 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) and statistical thermodynamics, in order to go beyond the essentially static pictures given by these methods.
In addition, computational tools allow to make use of the important information contained in massive sequence data of related molecules in the tree of life and help to understand what is essential in their active site structure and how it is modulated.
As such, homology modelling and molecular phylogeny techniques are routinely used to extend the scope of our studies,
while simulation of the transition path that "connect dots" between different conformational states of these macromolecule help understand the molecular origin and essential features of their function.
We also try to better understand the electrostatics properties of macromolecules and their interaction with the solvent and ligands, in order to predict their binding properties and inspire durg design.

When appropriate we study their structure in the context of their partners in larger macromolecular complexes and try to dissect the molecular interactions between them in order to understand possible emerging collective properties (systems biology).

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

N.B. Due to some security issues in our servers, most of our web services are not available outside campus.
We apologize for this situation and are working on a new and secure implementation of our web servers.

Publications by year (2009-2020)

2021

-New article by Dariusz Czernecki et al. accepted for publication on how bacteriophage S-2L manages to replace all adenines by amino-adenines in its genome (2-6 diaminopurine) to avoid the restriction enzymes of its bacterial host.

2020

-New article in Biomolecules by C. Samson et al. on the structures of key intermediates in the reaction of a DNA polymerase evolved to accept xeno-nucleotides and its substrates Ref.
This paper identifies for the first time a 1-nucleotide backtracked complex, on the pathway to the editing complex Text.

-New article in Phys. Rev. E with P. Koehl and H. Orland on the solution of the unbalanced Optimal Transport Problem with statistical physics methods Here.

-New article in PNAS by H. Hu et al. about the structures of both open and closed forms of a new bacterial pLGIC with two additional N-terminal domains and an unusual allosteric regulation at the supramolecular level (Ref and Text).

-New article in Acta Cryst D by Z. Fourati et al. on the vestibular allosteric binding site in pLGICs (GLIC) (Here).

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

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 Phys Rev E (PRE). See articles here, PRL.pdf and PRE.pdf.
We are working on applications of this method in the field of structural bioinformatics as well as IA.

-A structural model for the interaction of human Pol mu with an NHEJ junction containing a DNA double-strand-break, 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

-Dissection of the molecular mechanism of proton gating in GLIC in PNAS and PDF.

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

-Co-organization of a 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 Recomm by F1000)

-Review on TdT in Current Opinion in Structural Biology (on line and Recomm by 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 Recomm by 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 Recomm by 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, by J. Loc'h, S. Rosario and M. Delarue (Structure). See Recomm by 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 Molecular Dynamics 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).
This is the first structure of a polX in a complex with a broken DNA, showing how the two ends are brought together by a mold coming from the protein.

-Structure of a GLIC-GlyR chimera with P.-J. Corringer (PNAS, Feb 2015)

-Structural characterization of allosteric binding sites in the extracellular domain of GLIC (Acta Cryst D, March 2015) see Recomm by F1000

2014

-Structural basis for the gating mechanism in GLIC (PNAS, Jan 2014), see Recomm by F1000
This article provides the first pair of crystal structures of the same pLGIC in two different forms, open and closed, allowing for the first time to understand the gating mechanis at work in this family at the molecular level.

-A structural perspective in the pharmacology of pLGICs - a review (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 Recomm by F1000

-Snapshots of TdT caught in action: dynamical aspects of the two-metal-ion mechanism by 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

-Structure of a locally-closed form for GLIC in Nature Structural Molecular Biology 2012, see Recomm by F1000

2011

-Atomic structure of a complex of general anesthetics with GLIC is published in Nature in 2011, Recommended by F1000
This is the first atomic structure of a general anesthetics bound to an ion channel.

-A web site and software to analyze SAXS data and fit them to molecular models by Fred Poitevin et al. in NAR web site issue.

2010

-1 micro-second long Molecular Dynamics simulation of GLIC with Marc Baaden in 2010, see Recomm by F1000

-A meeting in I. Pasteur (Paris) was organized in the framework of our France-Stanford exchange Program

-Atomic structure of the extra-cellular domain of pentameric ligand-gated ion-channel in J. Mol. Biol. JMB

2009

- First Atomic structure of the open form of a pentameric liagnd-gated ion channel (GLIC), with P.J. Corringer in Nature 2009, see Recomm by F1000

-Extensive mutational analysis of TdT and different ways to transform it into a template-directed DNA polymerase by F. Romain et al. in Nucleic Acids Research NAR

-The AquaSol model was extended to include solvent-solvent interactions in PRL, see Recomm by F1000.
It goes beyond the Poisson-Boltzmann treatment of macromolecular electrostatics by allowing a variable solvent density, treated as an assembly of dipoles amid free ions and surrounding the charged solute.

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