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PhD Thesis Offer in Marseille - BIP Lab (Application deadline : 6th June 2018)

vendredi 18 mai 2018

PhD thesis title : Advanced EPR studies of molybdenum enzymes for CO2 valorization

Laboratory : Bioenergetics and Protein Engineering – BIP – Aix-Marseille University & CNRS (France)

Team : Biophysics of metalloproteins (Prof. B. Guigliarelli) -

Supervisor : Dr. Stéphane Grimaldi, HDR , Phone : +33 (0)4 91 16 45 57

Description of the PhD project :

Mononuclear molybdenum active sites in which the metal ion is coordinated by one or two pterin ligands play central biological roles [1]. They are found in a large family of enzymes that catalyze a wide diversity of redox and non-redox reactions including hydroxylations or oxygen or sulfur atom transfer. The ability of some members of the family (i.e. formate dehydrogenases or FDHs) to be able to reversibly convert CO2 in mild conditions into formate (HCOO-), a precursor for the synthesis of hydrocarbons, has attracted much attention in the context of the search for new energy sources alternative to fossil fuels. However, the understanding of the molecular factors that drive the reactivity, the efficiency, the specificity and the catalytic directionality of mononuclear molybdenum enzymes (MOEs) in general and of FDHs in particular remains limited.
The aim of this project is to address these issues by providing a detailed description of the molybdenum active sites in different catalytically-relevant or inhibited states of carefully selected MOEs. For this purpose, a state-of-the-art experimental approach based on multi-frequency EPR spectroscopy, including pulsed hyperfine spectroscopy (ESEEM, ENDOR, HYSCORE) will be used to characterize the magnetic properties of key Mo(V) intermediates, including the detection and analysis of weak magnetic and nuclear quadrupole interactions to nearby magnetic nuclei [2]. Uniform or specific isotope enrichment strategies of natural or engineered enzymes, or of their substrates or inhibitors will be developed to provide a deep understanding of the active site reactivity. The data will be interpreted by computer-assisted theoretical modeling relying on structure-based DFT calculations and/or QM/MM hybrid approaches. Such combination of approaches aims at providing new insights into how the protein environment tunes MOEs reactivity as well as clues for the rationale design of bio-inspired Mo-based artificial catalysts optimized towards the reduction of CO2 in mild conditions.
The student will be hosted in the BIP lab in Marseille for a 3-year PhD contract from Aix-Marseille to begin in October 2018. The BIP lab has a strong expertise in spectroscopic and theoretical studies of metallo-enzymes (see e.g. [3]). It hosts one of the major French EPR facilities of the national EPR network that includes continuous wave and pulsed EPR spectrometers operating at various frequencies (3 GHz, 9 GHz, 34 GHZ and 94 GHz) and equipped with multi-resonance capabilities.

Candidate profile :

The applicant must have a Master of Science in Chemistry or Physics with honors and some experience in spectroscopy. An interest in theoretical approaches such as DFT calculations is welcome. Highly motivated, independent and dynamic, he/she should be able to work in a multidisciplinary team.
Please send applications including (i) a detailed CV, (ii) official transcripts of master and undergraduate studies, (iii) an application and motivation letter, and (iv) a recommendation letter of the Master’s internship supervisor by e-mail at Stéphane Grimaldi

Application deadline : 6th June 2018 – Interview in Marseille (doctoral school) : 19th June 2018.

References :

[1] S. Grimaldi, B. Schoepp-Cothenet, P. Ceccaldi, B. Guigliarelli & A. Magalon (2013) Biochim. Biophys. Acta - Bioenergetics, 1827, 1048-1085
[2] E. L. Klein, A. V. Astashkin, A. M. Raitsimring & J. H. Enemark (2013) Coord. Chem. Rev., 257, 110-118
[3] J. Rendon, F. Biaso, P. Ceccaldi, R. Toci, F. Seduk, A. Magalon, B. Guigliarelli & S. Grimaldi (2017) Inorg. Chem., 56, 4422-4434

Detailed offer :

PDF - 173.1 ko

PhD Thesis Offer in Marseille - BiosCiences team (Application deadline : June 2018 the 5th)

jeudi 17 mai 2018

Experimental and theoretical investigation of polynuclear
bio-inspired copper complexes

Copper active sites play central biological roles, including electron transfer, dioxygen binding, activation and reduction, as well as denitrification processes. Enzymatic copper centers are extremely diverse in geometric and electronic structure, and range from mononuclear sites to dinuclear, trinuclear and tetranuclear clusters. The
accurate description of the magnetic and spectroscopic properties of these polynuclear sites, at different stages of the reaction cycle, is of high importance to get a better understanding of the structure-function relationships and catalytic mechanism.

In this project we aim at designing bioinspired polynuclear low molecular weight copper complexes, as well as at understanding their redox, spectroscopic, electronic and magnetic properties, in relation with the corresponding enzymatic systems. The ligands and bridging atoms will be modulated to exemplify the complexity observed in Nature and their reactivity in modeling reactions will be tested. The characterization of the complexes will rely on different techniques such as electron paramagnetic resonance (EPR), UV-visible, electrochemistry etc. A special emphasis will be dedicated to the use of theoretical approaches such as Density functional theory (DFT) for the description of the properties using spin-projection methods. [1] In some cases, the magnetic interactions and associated spectroscopic behavior become highly complex so that DFT calculations can produce inconsistent results.
Such limitations could be lifted by the use of advances theoretical approaches such as Density Matrix Renormalization Group (DMRG). This approach will be conducted in collaboration with a German group (Max Planck Institut, Mülheim/Ruhr, Germany). The proposed project therefore involves a combined experimental and theoretical
approach. Such combination of synthesis, spectroscopy and theory aims at understanding the properties and functions of the bioinorganic sites themselves, and finally to inform the synthesis of improved and potentially functional analogues of biological multicopper sites.

The student will be hosted in the BiosCiences group at iSm2 in Marseille for a 3-year PhD contract from Aix- Marseille to begin in October 2018. There is also the possibility to teach during this 3-year contract. The BiosCiences group will provide a multidisciplinary environment and has already strong expertise in combining both experimental and theoretical approaches to study bioinspired metal complexes as well as metal-containing enzymes.[2]

[1] a) D.A. Pantazis, M. Orio, T. Petrenko, S. Zein, E. Bill, W. Lubitz, J. Messinger, F. Neese, Chem. Eur. J., 2009, 15, 5108-5123.
b) M. Orio, D.A. Pantazis, F. Neese, Photosynth. Res., 2009, 102, 443-453. c) M. Orio, D.A. Pantazis, T. Petrenko, F. Neese,
Inorg. Chem., 2009, 48, 7251-7260.
[2] a) A. L. Concia, M. R. Beccia, M. Orio, F. Terra Ferre, M. Scarpellini, F. Biaso, B. Guigliarelli, M. Réglier, A. J. Simaan, Inorg.
Chem., 2017, 56, 1023-26. b) M. Eckshtain-Levi, R. Lavi, L. Benisvy, M. Orio Inorg. Chim. Acta, 2017, DOI :
10.1016/j.ica.2017.09.049. c) O. Cuzan, A. Kochem, A. J. Simaan, B. Faure, V. Robert, S. Bertaina, M. Giorgi, S. Shova, M.
Maffeï, M. Réglier, M. Orio, EurJIC, 2016, 5575-5584. d) N. El Bakkali-Tahéri, S. Tachon, M. Orio, S. Bertaina, V. Robert, T.
Tron, M. Réglier, P. Dorlet, A. J. Simaan Arch. Biochem. Biophys., 2017, 623-624, 31-41. e) M.-C.Kafentzi, M. Orio, M. Réglier,
S. Yao, U. Kuhlmann, P. Hildebrandt, M. Driess, J. Simaan, K. Ray, Dalton Trans., 2016, 45, 15994-16000.

copper complex, protein mimic, organic chemistry, coordination chemistry, spectroscopy, magnetism, quantum chemistry

Required skills
Background in organic synthesis and/or coordination chemistry
Knowledge in quantum chemistry and spectroscopy is welcome

Dr Maylis Orio & Dr A. Jalila Simaan
Aix Marseille University, CNRS, UMR 7313, BiosCiences team :
Application deadline : June 2018 the 5th

Detailed offer :

PDF - 41.2 ko

PhD Thesis Offer in Université Paris Descartes (2018-2019)

mercredi 9 mai 2018

Development and applications of EPR probes of oxidative stress.

The level of reactive oxygen species, such as superoxide anion and hydroxyl radical, is tightly regulated by antioxidant enzymes or small molecules in vivo. However, when the balance is lost, a situation of oxidative stress can occur in cells with accumulation of damages to proteins, lipids, and nucleic acids. These lesions can be analysed by ex vivo methods and oxidative stress is involved in a large number of pathological situations (inflammation, cancer, neurodegenerative diseases...). The non-invasive detection and mapping of oxidative stress in vivo would give valuable information on disease development and help develop diagnostic and therapeutic tools.
In recent years, we focused on developing new redox-sensitive probes derived from tetraethyl-substituted aminoxyl radicals (nitroxides) or hydroxylamines to monitor oxidative stress by differential measurements on pathological and control animals by electron paramagnetic resonance (EPR) spectroscopy. The previous PhD project allowed us to perform a structure-activity relationship study and to validate the hypothesis with the lead compound on cultured cells. This opens the way for the current PhD project focused on further probe optimization and in vivo applications.

Detailed offer :

PDF - 164.3 ko

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