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overview

My research focusses on understanding biomolecular systems at an atomic level using computational biophysical approaches. My primary interest lies in membrane biology: the properties of lipids and membranes and their interactions with the environment and other (bio)molecules. In particular, using molecular dynamics simulation, I have examined the properties of a range of sterols and prokaryotic lipids involved in mechanisms leading to bacterial virulence, resilience and resistance to antimicrobials (e.g. antibiotics and disinfectants). I am also interested in the interplay between transmembrane proteins and their membrane environment.

With my research, I aim to gain insight into the properties of lipids, how these can modulate the structure and the dynamics of membranes, and affect the structure and function of membrane proteins, antimicrobial peptides and more broadly membrane-active (bio)molecules.

research interets

properties of bacterial, archaeal and eukaryotic lipids: towards realistic models for biological membranes

Lipids are the building blocks of biological membranes. Not only do they play a structural role in delineating cells and organelles, but also participate in and regulate critical cellular processes through the modulation of essential membrane properties. Lipid bilayers consisting of phospholipids in which the two fatty acyl chains are linear (saturated or unsaturated) have been extensively examined as models for biological membranes both experimentally and in simulation. However, the repertoire of membrane lipids is far more diverse. While linear-chain fatty acids are typical of eukaryotic membranes, branched-chain fatty acids are widespread in bacterial and archaeal membranes where their concentration often exceeds that of linear-chain fatty acids. Alongside branched-chain fatty acids are the pentacyclic triterpenoids hopanoids that are also unique to bacteria. Given their structural similarity to sterols, hopanoids have long been assumed to be functional analogues to sterols in bacteria. Branched-chain fatty acids and hopanoids have been suggested to play a fundamental role in bacterial virulence, resilience and resistance to unfavourable environments (e.g. low or high temperature, low pH, high concentration of toxic compounds including antibiotics) but, surprisingly, their properties are still largely unknown. It is only by understanding the properties of a wide range of lipids in detail that realistic models for specific bacterial, archaea and eukaryotic membranes can be developed and used for further studies.

development and validation of force-field parameters for lipids

Force-field parameters for phosphatidylcholines, an especially common class of lipids in eukaryotic membranes, that have been widely used in the GROMACS community and proposed by Berger et al. in 1997 (Biophys. J. (1997), 72, 2002–2013), are based largely on the outdated GROMOS87 parameter set. I have examined the ability of the GROMOS 53A6 forcefield to reproduce the structural and dynamical properties of a range of phosphatidylcholine bilayers (namely DLPC, DMPC, DPPC, DOPC and POPC) in a fluid phase. The simulations show that by varying the van der Waals interactions between the choline methyls and the phosphoryl (i.e. non-ester) oxygens in the phosphate group, it is possible to obtain a phosphatidylcholine bilayer in a liquid-crystalline phase well suited to biologically relevant simulations. The force field was extensively validated using a range of structural and dynamical properties that were compared against experimental data, and by simulating the spontaneous assembly of lipids into a bilayer starting from a random mixture of lipids in water. The new parametsr for lipids have been included in the latest revision of the GROMOS force field (54A7).

understanding the mechanism of action of antimicrobial peptides

Membrane-disrupting antimicrobial peptides are found throughout the animal and plant kingdoms where they are vital components of the innate immune system of complex multicellular organisms, including humans. Membrane-disrupting antimicrobial peptides bind to and disrupt bacterial membranes with a highly specificity. They have remained effective against bacteria on an evolutionary timescale and have thus the potential to be exploited into a new class of therapeutics. The mechanism underlying the mode of action of antimicrobial peptides and the membrane specificity is still poorly understood. In particular, it is unclear how the lipid composition (nature of the lipid head groups, presence of branching group in the lipid tails) can determine the sensitivity of a membrane to different antimicrobial peptides. The aim of this project is to determine the properties of both the target membranes and the antimicrobial peptides that affect the activity of antimicrobial peptides.

understanding the mechanism of activation of cytokine receptors

Tissue homeostasis, including cell proliferation, differentiation and survival is primarily regulated by cytokines. As a consequence, cytokines and their receptors are key factors in tumorigenesis. In particular, the receptors of the epidermal growth factor (EGFR), growth hormone (GHR), erythropoietin (EPO) and prolactin (PRLR) play critical roles in frequent types of cancer. Little is currently known in regard to the precise mechanism by which the binding of a cytokine to its cell-surface receptor transmits a signal across the plasma membrane through conformational changes within the extracellular and transmembrane domains. Elucidating how the binding of a given cytokine to the extracellular domain of its receptor triggers a signal is crucial, not only for our basic understanding of cell signalling at a molecular level, but also for the development of new, efficient and selective anti-cancer agents.

my PhD thesis (2002–2005)

In 2005, I was awarded my degree of Doctor of Philosophy (PhD) from the Joseph Fourier–Grenoble I University in Grenoble (France). My PhD thesis is entitled "Structure, molecular dynamics and selectivity of copper and mercury metallochaperones" and was carried out at the Molecular and Cellular Biophysics Laboratory of the French Commissariat à l'Énergie Atomique (CEA), Grenoble (France).
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