MultiMics

The aim of our project is to provide molecular models of biomolecular self-organisations in cells. In this context, we intend to develop reduced models of biological macromolecules which will allow to efficiently simulate their dynamics and better understand the physical driving forces of the formation of large biomolecular assemblies. We plan to apply these methodological developments to the polymerization of the tubulin protein into microtubules and to the specific association of tubulin with other proteins which regulate the microtubules formation. With both theoretical and experimental approaches, a first part of our project will consist in solving the three-dimensional structure and studying the dynamics of the tubulin complexed with the CPAP protein that is known to inhibit the formation and/or destabilize the microtubules structure. The experimental study will be mainly performed with NMR and biochemical techniques. For the theoretical approach, we will use a « coarse grained » protein model, defined at the residue-scale, and that will include a simplified description of the internal flexibility. This work on the tubulin complexes will also give us the opportunity to test the reliability of our model by comparing its predictions with experimental data. The second part of our project will consist in developing a « super coarse grained » protein model, on the tubulin domain-scale, in order to simulate the microtubules formation and stability. Indeed, this methodological development is necessary to allow an efficient modelling of several hundreds of proteins over time-scales of several microseconds or more. The different steps to build the model will be: (1) To define tubulin quasi-rigid domains using a low frequency normal modes analysis. (2) To determine the van-der-Waals and electrostatic effective interactions between domains, using an underlying model. (3) To implement this « super coarse grained » protein description in a brownian dynamics algorithm or a similar simulation technique. Using this model, we plan to analyze the various energy contributions to the stability of microtubules and to study the mechanism of their formation.