Call for applications

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Biotechnology and Applied Pharmacology Laboratory (LBPA) localised in Ecole Normale of Cachan (France), is seeking Post Doctoral fellows to join the group Molecular Modeling and Structural Bioinformatics .

The laboratory's research focuses on the comparative study of HIV integrase from different viral strains, subtypes and their drug-resistant mutants in order to identify the relationship between a given strain and the selection of a specific mutation.To study these phenomenon, we use in silico methods including secondary structure prediction, modeling of 3D structure, molecular dynamics (MD) simulations and molecular docking.

 

Description of the project 1

Study of the determinants of resistance to anti-integrase inhibitors: Polymorphisme - resistance pathways relationships.

We recently demonstrated that the Raltegravir (the first and unique antiretroviral drug targeted IN) failure is associated with IN mutations following two distinct genetic pathways, involving either the N155H or Q148K/R/H (Malet et al. in Ant. Microb.Agent Ther ., 2008). We do not know the factors that determine these pathways which seem independent and exclusive. This project, proposed in collaboration with the department of clinical virology at the CHU Pitié-Salpêtrière (Paris), aims at addressing the impact of factors related to the virus, as the polymorphism of the IN and/or the virus subtype; the interaction with the reverse transcriptase or pharmacological factors related to the host, in the selection of this pathway. Recently, we compared the sequence of amino acids IN subtypes B and CRF02_AG and we identified that naturally occurring variations in the CRF02_AG, could have an impact on the susceptibility inhibitors IN ( Malet et al. in J.Med.Viro l. 2008). The sequences of ARV naive patients infected by different subtype virus (CRF_02, CRF_06, C, etc...) will be collected, analyzed and used as templates for the molecular modeling of IN. We will study the influence of these polymorphisms on the 3D structure of the target using theoretical model that we have proposed for the molecular origin of the resistance (Tchertanov et al., submitted).

 

Description of the project 2

Modeling of nucleoprotein complexes, IN, H-NS and it analogues

A significant fraction of nucleoproteins (viral and not viral) do not fold into stable 3-D structure, showing partial or complete unfolding. A key feature of this family is their capacity to undergo a disorder-to-order transition upon interaction with a physiological partner. The mechanisms governing protein folding upon interaction, in particular the extent to which recognition elements are preconfigured prior to formation of molecular complexes, provide difficulty to resolve in highly flexible systems. Therefore, extensive in silico study including secondary structure and folding prediction, 3-D structural modeling by homology, dynamic molecular simulations, modeling of quaternary structure and recognition properties characterization, contribute vigorously for understanding of such systems function.

Our previous studies allowed bringing the new elements on the structure of native and mutated IN (Tchertanov et. al., Febs Journal 2007) . We were able to show the specific character of the DNA bases recognition by the catalytic loop (Tchertanov et al. In Silico Study Suggests that Raltegravir-Resistant Mutations Modify the DNA Recognition Properties of HIV-1 Integrase. 6 th Drug Resistance Workshop, Budapest, 26-28 March 2008, http://www.hivpresentation.com/index.cfm?vID=09B46249-423A-F6F7-CC77692663D017D9. To determine better the target against which it will be more advantageous to draw new potential therapeutic agents susceptible to thwart the phenomenon of the resistance, we will to model the IN/DNA complex. This modeling would be done in two steps: (i) building of full-length IN using partial IN structures with applying molecular dynamics (MD) (CHARMm); (ii) building of the IN/DNA model by docking (SYBYL) with considering the experimental biochemical constrains and our data characterized the selective recognition of the DNA bases by IN.

Our other strategy of the IN/DNA modeling is based on the fitting of partial structures of IN and DNA on the 3D map of the low resolution electron microscopy (EM) density obtained by Marc Yeager (SRI, USA). This strategy will be realized in the collaboration with J. Navaza (IBS/LMES, Grenoble).

 

Post-Doctoral position

We are looking for post-doctoral scientist interested in working on structural bioinformatics/molecular modelling and/or computer assisted rational design of protein inhibitors. The candidates should have knowledge and experience in indicated disciplines. Experience in MD simulations will be appreciated.

PhD Fellowship

We are looking for students interested in doing a PhD in Molecular Modelisation and Structural Bioinformatics. The candidates should have computational experience and Physics/Biologie/Chemistry background.

Contact : Dr. Luba Tchertanov