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Doctoral thesis offer M/F. "Spinning at molecular scales: modeling the dynamics of the flagellar engine"

This offer is available in the following languages:
Français - Anglais

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General information

Reference : UMR5221-NILWAL-001
Workplace : MONTPELLIER
Date of publication : Monday, July 20, 2020
Scientific Responsible name : John Palmeri, Nils-Ole Walliser
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 September 2020
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly

Description of the thesis topic

The Bacterial Flagellar Motor (BFM) is a macromolecular protein complex embedded in the bacterial membrane capable of performing rotary motion in both senses with frequencies of about 100 Hz. It is attached to a long filamentous flagellum whose rotation enables the bacteria to perform a directed movement in viscous media.

The BFM's motion is one of the rare examples of continuous rotation around an axis one can find in living systems. Even though it is widely studied, the dynamically rich biological function of the motor and the biophysical principles responsible for its torque generation are not fully understood.

Two aspects of this system are particularly remarkable and demand further investigation. First of all, the BFM is capable of adapting its performance depending on the externally imposed torque (mechanosensitivity), by dynamically assembling and disassembling motive units. Second, the BFM couples to other intracellular processes like cell respiration and charge transport on the membrane. To turn, it consumes the transmembrane electrochemical potential difference due to the concentration gradient of ions (protons or, more rarely, sodium ions) across the internal membrane. This so-called Proton Motive Force (PMF) is established and maintained by cell respiration, and it can remarkably attain a few hundreds of millivolts.

At the interface between experimental and theoretical biophysics, our project aims at unraveling the molecular mechanisms and the fundamental principles responsible for the dynamic rotation of single motors on living E.coli cells.

Based on the results of single-molecule techniques conducted by our experimental collaborators at CBS, we will study the aspects mentioned above within the theoretical framework of statistical kinetics and mechanics. Furthermore, we will employ numerical and stochastic simulations as well as analytical and numerical methods for stochastic processes to model the ability of the system to adapt to changing external conditions and the dynamical coupling of the BFM with its cellular environment. Our approach will exploit the predictive strength of coarse-grained modeling in unraveling the properties emerging from the interaction of the different components of the system. But, where needed to gain insights on the mechanics of torque generation, we will dwell into the details of a mechanochemical description of the single macromolecular components at the nanoscopic scale.

PROFILE SOUGHT. We are looking for candidates willing to pursue theoretical research in a transdisciplinary context at the interface between physics and biology. Candidates should have a practical knowledge of PDEs, statistical mechanics and diffusion processes. Programming skills (Python or C) and experience with a symbolic and numerical computing environment (Mathematica, Sagemath, Matlab / Octave, etc.) will be appreciated. Candidates should have a Master's degree in physics, biophysics or physical chemistry (or related disciplines).

Level of French required: Intermediate: You can speak the language comprehensibly, coherently and confidently on everyday topics that are familiar to you.

Level of English required: Elementary: You can understand the language in basic everyday situations if the speaker speaks softly and clearly. You understand and use simple expressions.

OBJECTIVE AND CONTEXT. To analyse, model and understand the functioning of the bacterial flagellar motor, understand its mechano-sensitivity, understand the physical principles of how molecular machines work, analyse data and interact with experimenters.

Research at the physical-biological interface on a model system for biology and of great importance to understand also the bacterial response to external stimuli (e.g. chemotaxis).

METHODOLOGY. Statistical kinetics and statistical mechanics; gas-on-grid approaches. Numerical and stochastic simulations; analytical, semi-analytical and numerical methods for stochastic processes (abnormal diffusion), EDP.

EXPECTED RESULTS. To understand the stochastic dynamics of the rotor-stator assembly which is at the heart of the operation of the flagellar machine, to understand the origin of mechano-sensitivity, to understand the physical principles of operation of molecular machines. To understand the dynamic coupling of the BFM with its cellular environment (cellular respiration and membrane transport of electrical charges.

REFERENCES.
Berg, H. C. (2003). The rotary motor of bacterial flagella. Annual review of biochemistry, 72.

Mandadapu, K. K., Nirody, J. A., Berry, R. M., & Oster, G. (2015). Mechanics of torque generation in the bacterial flagellar motor. Proceedings of the National Academy of Sciences, 112(32), E4381-E4389.

Nirody, J. A., Sun, Y. R., & Lo, C. J. (2017). The biophysicist's guide to the bacterial flagellar motor. Advances in Physics: X, 2(2), 324-343.

Nord, A. L., Gachon, E., Perez-Carrasco, R., Nirody, J. A., Barducci, A., Berry, R. M., & Pedaci, F. (2017). Catch bond drives stator mechanosensitivity in the bacterial flagellar motor. Proceedings of the National Academy of Sciences, 114(49), 12952-12957.

Wadhwa, N., Phillips, R., & Berg, H. C. (2019). Torque-dependent remodeling of the bacterial flagellar motor. Proceedings of the National Academy of Sciences, 116(24), 11764-11769.

Work Context

The thesis will be supervised by John Palmeri and Nils-Ole Walliser, Laboratoire Charles Coulomb (L2C), University of Montpellier.

The candidate will join the research group "Complex Systems and Nonlinear Phenomena" at the Charles Coulomb Laboratory (L2C). The L2C is a joint research unit (UM-CNRS), located on the campus of the University of Montpellier (UM), and represents an international scientific environment dedicated to research in applied and fundamental physics, and to research at the interface between physics and biology.

The project will be carried out in collaboration with Francesco Pedaci and Ashley Nord from the "Centre de Biochimie Structurale" (CBS) Montpellier. This thesis is funded by the ANR-CNRS project 'FlagMotor'.

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