PHD2022-11
Physical, mathematical and computational modelization of two molecular machines
Host laboratory and collaborators
Alphée MICHELOT (IBDM) / alphee.michelot@univ-amu.fr
Tâm MIGNOT (LCB) / tmignot@imm.cnrs.fr
Abstract
Molecular machines and motors allow cells to perform different functions by using the energy produced by ATP or GTP hydrolysis. While some proteins, such as the myosins in our muscles, convert ATP energy into mechanical work on their own, other motors require the coordinated action of multiple proteins. For these systems, molecular mechanisms at play are misunderstood because they emerge from complex interaction networks yielding collective behaviors.
This project proposes to develop new tools and methods to address this problem by comparing two model systems. The first model is the assembly of the actin cytoskeleton, which requires several proteins and ATP to sustain efficient force generation over long periods of time. The second model is a molecular oscillator, which uses GTP to promote the spatial activation of motility in bacteria.
Keywords
Dynamic systems, molecular oscillators, ATP and GTP, biophysics, mathematics and computational biology, actin cytoskeleton
Objectives
The objective of this project is to integrate biophysical, mathematical and computational approaches to understand conserved molecular mechanisms in biology. The recruited student will be working in close collaboration with experimentalists, in order to obtain the data necessary for the implementation of its models, and reciprocally to guide the experimentalists towards the development of more efficient reconstituted systems.
Proposed approach (experimental / theoretical / computational)
The student will be working in close interaction with experimentalists.
From the experimentalists, the student will be in charge of collecing information relative to the biochemical and biophysical properties of the proteins at play, in order to complexify progressively the developed models. For the simplest molecular systems, it will be possible to solve sets of differential equations in order to predict the evolution of the systems over time. For more complex situations (in particular for non-markovian processes), it will be necessary to develop more complex in silico tools to predict the stochastic evolution of these systems.
Reciprocally to the experimentalists, the student in charge will be expected to discuss and find ways to test the predictions of its models in the lab. We expect that results from the models will enable us to pregressively reconstitute some of these complex molecular mechanisms in vitro.
Interdisciplinarity
This project provides an opportunity for a curious student to develop skills in biology (by gaining an in-depth understanding of two mechanisms essential to many biological processes), in biophysics (by seeking to understand the physical principles underlying two biological machines, using ATP and GTP as energy sources), in biochemistry (by understanding how multiple individual interactions between molecules of interest are coordinated to perform a desired function), and computer science (in order to propose powerful computational methods and tools to carry out these applications).
Expected profile
This project is adapted to a student from a physics, mathematics or computational science background, with basic knowledge in biology. The project will eventually require a good level in multiple disciplines, so the recruited student is expected to be curious and motivated in gaining knowledge in the disciplines that would have been less covered in the course of his curriculum.
Host teams are strongly interdisciplinary, so the student will have to interact with many different colleagues and should have the personality to do so.
Is this project the continuation of an existing project or an entirely new one? In the case of an existing project, please explain the links between the two projects
This project is requested to strenghten an existing collaboration between the Michelot and Mignot labs. Experimental data accumulate but the two teams lack of a specialized student with time to analyze and integrate this knowledge into powerful biophysical models. Swapnesh Panigrahi a biophysicist with a background in theory will help mentor the student. Céline Dinet a post-doc will also contribute to the experimental aspects of the project.
2 to 5 references related to the project
Actin cytoskeleton:
1. Experiment, theory, and the keratocyte: An ode to a simple model for cell motility. Mogilner A, Barnhart EL, Keren K. Semin Cell Dev Biol. 2020 Apr;100:143-151.
2. A functional family of fluorescent nucleotide analogues to investigate actin dynamics and energetics. Colombo J, Antkowiak A, ..., Michelot A. Nat Commun. 2021 Jan 22;12(1):548.
Molecular oscillator:
3. A gated relaxation oscillator mediated by FrzX controls morphogenetic movements in Myxococcus xanthus. Guzzo M, Murray SM, Martineau E, Lhospice S, Baronian G, My L, Zhang Y, Espinosa L, Vincentelli R, Bratton BP, Shaevitz JW, Molle V, Howard M, Mignot T. Nat Microbiol. 2018 Aug;3(8):948-959.
4. Linking single-cell decisions to collective behaviours in social bacteria. Dinet C, Michelot A, Herrou J, Mignot T. Philos Trans R Soc Lond B Biol Sci. 2021 Mar 15;376(1820):20190755.
5. The polar Ras-like GTPase MglA activates type IV pilus via SgmX to enable twitching motility in Myxococcus xanthus. Mercier R, Bautista S, Delannoy M, Gibert M, Guiseppi A, Herrou J, Mauriello EMF, Mignot T. Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28366-28373.
3 main publications from each PI over the last 5 years
Michelot lab:
1. A functional family of fluorescent nucleotide analogues to investigate actin dynamics and energetics. Colombo J, Antkowiak A, ..., Michelot A*. Nat Commun. 2021 Jan 22;12(1):548.
2. Mechanical stiffness of reconstituted actin patches correlates tightly with endocytosis efficiency.
Planade J, Belbahri R, ..., du Roure O*, Michelot A*, Heuvingh J. PLoS Biol. 2019 Oct 25;17(10):e3000500.
3. Sizes of actin networks sharing a common environment are determined by the relative rates of assembly. Antkowiak A, ..., Michelot A. PLoS Biol. 2019 Jun 10;17(6):e3000317.
Mignot lab:
1. A Tad-like apparatus is required for contact-dependent prey killing in predatory social bacteria. Seef S, Herrou J, de Boissier P, My L, Brasseur G, Robert D, Jain R, Mercier R, Cascales E, Habermann BH, Mignot T. Elife. 2021 Sep 10;10:e72409. doi: 10.7554/eLife.72409.
2. The polar Ras-like GTPase MglA activates type IV pilus via SgmX to enable twitching motility in Myxococcus xanthus. Mercier R, Bautista S, Delannoy M, Gibert M, Guiseppi A, Herrou J, Mauriello EMF, Mignot T. Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28366-28373.
3. A gated relaxation oscillator mediated by FrzX controls morphogenetic movements in Myxococcus xanthus. Guzzo M, Murray SM, Martineau E, Lhospice S, Baronian G, My L, Zhang Y, Espinosa L, Vincentelli R, Bratton BP, Shaevitz JW, Molle V, Howard M, Mignot T. Nat Microbiol. 2018 Aug;3(8):948-959.