Modularité et Désordre Intrinsèque : Dialogue Moléculaire de Protéines Archétypales avec leurs Partenaires Physiologiques

Most proteins are assemblies of structurally and/or functionally independent or quasi-independent modules. IDPs are proteins that manifest such properties and can be either fully disordered or accompanied by well-ordered regions. These proteins play vital roles in various biological processes.By employing numerical (in silico) approaches, including 3D modeling and extended molecular dynamics simulations, we examined two archetypical IDPs: the receptor tyrosine kinase (RTK) KIT and the human vitamin K epoxide reductase complex 1 (hVKORC1). These proteins are critical therapeutic targets in cancer and blood coagulation, respectively. By generating full-length dynamical models of their wild type and mutant forms, we characterized their intrinsic and dynamical properties (DYNASOME) and studied their interactions with their physiological partners (INTERACTOME) to investigate the initiation of signaling pathways regulated by RTK KIT and the thiol-disulfide exchange reaction leading to hVKORC1 activation.Overall, this research offers a basis for further exploration on protein activation and resistance mechanisms, particularly in terms of allosteric regulation. Moreover, the obtained data will be useful for potential therapeutic advancements (allo- network drugs). Ultimately, the strategies and protocols established in this study can be extended to the investigation of other modular IDPs.