PhD in molecular simulation of membrane proteins (M/F)

Job Description

Thesis Subject

Cytochrome bd oxidases are a family of membrane proteins who catalyze the reduction of oxygen in water. They are present only in prokaryotic species. In addition to this catalytic reduction of oxygen, cytochrome bd oxidases appear to play a crucial role in protecting prokaryotes from oxidative stress, in bacterial virulence, adaptability, and antibiotic resistance.

Until now, cytochrome bd structures from from four different species (E. Coli, Mycobacterium smegmatis, Mycobacterium tuberculosis et Corynebacterium glutamicum) are available. The first structure has been obtained in 2016. All of these structures possess three heminic cofactors : 2 b-type hemes and on d-type heme. The spatial configuration of the three hemes is however different among the species., as well as the order of their redox potentials [1,2]. A recent study from Murali et al. [3] has confirmed the great structural diversity in the cytochrom bd family. Moreover, the analysis of the structures has allowed to invalidate the putative mechanism of O2 reduction between heme b595 and heme d. The detailed understanding of the catalytic mechanism is thus still missing, as well as the understanding of the role of the diversity observed among species. It is however aknowledged that the electrons needed to reduce are primarily brought by quinones (in their quinol form) who transfer them (one by one) to one of the b heme (the most accessible to the solvent). The electrons are then transferred between the hemes to heme d, where the final reduction of O2 takes place.

We studied cytochrome bd-I from E. coli using molecular simulations to understand electron transfer between the second heme b and heme d [4]. To this end, we performed molecular dynamics simulations of the protein within a realistic membrane environment in multiple redox states, in order to evaluate the thermodynamics of the process. We now intend to further our understanding of how this cytochrome functions by studying the various steps of the enzymatic mechanism, from quinone binding to final dioxygen reduction.

This PhD project is in the direct continuation of our first works and its aim is to caracterize the various steps of the catalytic mechanism of oxygen reduction by cytochromes bd, with the E. Coli cytochrom bd-I protein as a first example. This work will require the use of a large panel of molecular modeling tools, from the construction of 3D models of protein complexes inserted in membranes to quantuim chemistry calculations, including classical molecular dynamics simulations. The major points that will be under scrutiny during the project are the following:
1. Determination and characterization of the binding site of quinones to cytochrome bd, close to the first heme b. To this end, we will perform microsecond-long molecular dynamics simulations to evaluate the relevance of plausible binding poses.
2. Study of the initial electron transfer between the quinone (in its quinol form) and the first b heme. For this, we will need to perform molecular dynamics simulations in a QM/MM framework in order to take into account the proton transfers that are couple to the electron transfers.
3. Study of the reaction mechanism of the final reduction of oxygen into water, with the use of molecular dynamics simulations in a QM/MM framework.

This PhD project is part of the ANR project UTAH, in close collaboration with a research team at Strasbourg University and a second one at Aix-Marseille University. The results will be correlated to experimental (IR and EPR spectroscopic data) and theoretical results (magnetic properties calculation) obtained in the partner teams and a theory/experiment dialog will allow to enrich the project.

The person recruited will have the opportunity to use a large panel of theoretical chemistry and molecular modeling methods applied to the study of biomolecules. She will find in the group of theoreticians at ICP a good scientific environment to gain new competences. The members of the group indeed possess a good experience in the domain of molecular simulation of physico-chemical processes in proteins. The PhD student will have access to the computer cluster of the lab and to national supercomputers of the GENCI.

[1] R. Murali, R.B. Gennis, J. Hemp, Evolution of the cytochrome bd oxygen reductase superfamily and the function of CydAA' in Archaea (2021) ISME J. 15(12) : 3534-3548.
[2] A. Nikolaev, S. Safarian, A. Thesseling, D. Wohlwend, T. Friedrich, H. Michel, T. Kusumoto, J. Sakamoto, F. Melin, P. Hellwig (2021) Electrocatalytic evidence of the diversity of the oxygen reaction in the bacterial bd oxidase from different organisms, Biochim. Biophys. Acta, Bioenerg. 1862(8) : 148436.
[3] R. Murali, R.B. Gennis, J. Hemp, Evolution of the cytochrome bd oxygen reductase superfamily and the function of CydAA' in Archaea (2021) ISME J. 15(12) : 3534-3548
[4] R. Siddeeque, B. Etcheverry, C. Cattin, J. Deviers, F. Melin, P. Hellwig, F. Cailliez, A. de la Lande, Computational study of heme b595 to heme d electron transfer in E. coli cytochrome bd-I oxidase (2025) J. Chem. Inf. Model. 2026, 66, 3, 1757–1768

Your Work Environment

The project will take place at Institut de Chimie Physique of Université Paris-Saclay, in the ThéoSim group. The direction of the PhD will be performed by Dr Fabien Cailliez (fabien.cailliez@universite-paris-saclay.fr, HDR) with a co-direction by Dr Aurélien de la Lande (aurelien.de-la-lande@universite-paris-saclay.fr, HDR).
The recruited person will belong to the 2MIB Doctoral school of Université Paris-Saclay.
The PhD will take place as part of the UTAH ANR project, in interaction with research teams in Strasbourg and Marseille.

Compensation and benefits

Compensation

2300 € gross monthly

Annual leave and RTT

44 jours

Remote Working practice and compensation

Pratique et indemnisation du TT

Transport

Prise en charge à 75% du coût et forfait mobilité durable jusqu’à 300€

About the offer

About the CNRS

The CNRS is a major player in fundamental research on a global scale. The CNRS is the only French organization active in all scientific fields. Its unique position as a multi-specialist allows it to bring together different disciplines to address the most important challenges of the contemporary world, in connection with the actors of change.

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