Structural Dynamics of Macromolecules - CNRS URA2185  


  Annual Report


The aim of the group is to understand at the molecular level the nature and energetics of ligand binding in validated drug targets of various pathogens, using X-Ray crystallography and computational structural biology. In addition, we have embarked in a larger project aimed at understanding the nature of intermediates along the reaction pathway of a catalytic cycle for fundamental objects of molecular biology, such as DNA polymerases.

Experimental results

a) Structure-inspired drug design (coll. V. Stoven et al, I.P.)

The crystallographic structure of T. cruzi 6-Phosphogluconolactonase (6PGL) involved in the essential pentose phosphate metabolic pathway was refined at 2.1 Angstrom. The structure was compared to existing related structures in the PDB to narrow down the possible models for substrate binding and catalysis (online in JMB since Nov 22, 2006). In addition, diffraction data on a different crystal form obtained in the presence of either the product or a known inhibitor were recently refined; the results, as well as an in-depth analysis of common water molecules in the active site, will be the input of a new round of in silico docking studies of substrates and potential inhibitors.

b) Structural studies of human pol μ (coll. F. Rougeon, I.P.)

Pol mu is a recently discovered DNA polymerase involved in Non-Homologous End-Joining repair system of DNA double-strand breaks. We have devised a way to study in vitro substrates with interrupted templates strands (normally held in place by Ku 70/80) by using chemically modified oligonucleotides that mimic this effect, as suggested by our modelling studies based on the structure of TdT (Delarue et al., 2002). We have shown that pol mu is indeed accepting these substrates and is then able to incorporate dNTP in a template-dependent fashion. We are currently trying to crystallize the protein in a complex with one member of this family of substrates.

Computational results

a) NOMAD-Ref

We use Normal Mode Analysis and the Elastic Network Model to try and understand large amplitude movements and structural transitions in Macromolecules of virtually any size. Following our proof-of-principle article (Delarue and Dumas, P.N.A.S., 2004), we have further developed the refinement of structural models along Normal Modes in the presence of X-Ray data or Cryo-EM data (Lindahl et al., NAR, 2006). See

b) PDB_Hydro

We have devised and implemented a new method to calculate electrostatics properties of macromolecules and their complexes in a dipolar solvent of variable density (or a mixture thereof) thereby generalizing the Poisson-Boltzmann Equation method (Azuara et al., NAR, 2006).

c) Conformational transitions (Coll. S. Doniach, Stanford).

We have pursued our work aiming at producing physically exact trajectories along the reaction pathway between two known structural forms of the same macromolecule. The program will be put on-line in 2007. Full studies of the translocation step of the catalytic cycle for DNA-dependent DNA polymerases have been performed and analyzed.


Prediction of the well (blue) and poorly (red) hydrated surface of M. tuberculosis TMP kinase by the web site


Publications 2006 of the unit on Pasteur's references database

Activity Reports 2006 - Institut Pasteur
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