Bieau

Water is the matrix of life on our planet. It plays fundamental and versatile roles in most biological processes on the cellular and the molecular levels, making water the most important of all biological molecules. Hydration water is indispensable for the structure, stability, dynamics and function of biological macromolecules. It is an integral part of macromolecular structures, participates in protein function, modulates functionally important macromolecular motions and mediates macromolecular recognition. Awareness has grown over the last ten years that biological water is not a passive bystander and efforts have multiplied internationally to unravel the complex mysteries of water's interaction with biological molecules. Yet, a profound understanding and a detailed description of the structural and dynamical properties of biological water and their impact on the various biological processes at different length and time scales remain elusive. Our project addresses two virgin issues. First, we will explore the role of hydration water in a new class of medically relevant proteins, in so-called intrinsically unfolded proteins (IDP). IDP lack a well-defined three-dimensional structure in their native state, yet they fulfill specific biological roles and often fold upon binding a partner protein. In particular, we will work with the human tau protein that forms so-called neurofibrillary tangles in Alzheimer diseased brains. En route to meeting this first objective, a first step will thus be to address hydration-water dynamics around the different types of amino acids. As a second objective, we address protein dynamics in a water and solvent-free protein liquid; a protein-polymer hybrid invented by Prof. Mann (Bristol University). Mann's laboratory made the stunning observation that the polymer coating ensures protein activity even in the absence of water and solvent. Can polymer coating replace water in its role as the matrix of life ? Our second objective will help answering this question. In order to reach our two objectives, we propose to apply a synergistic combination of computational and experimental biophysical and biochemical techniques, including molecular dynamics simulations, neutron spectroscopy, THz spectroscopy, small angle X-ray scattering, site directed mutagenesis and protein perdeuteration. A pluridisciplinary team of biologists, chemists, biochemists and biophysicists will tackle the two objectives by using world-class equipment such the ESRF and the ILL Neutron Reactor in Grenoble, the European laboratory for protein deuteration (DLAB) and the world's most powerful THz laser at Bochum University. Gaining insight into the dynamical and structural impact of hydration water on intrinsically disordered proteins (first objective of our project) will extend our fundamental knowledge on the role of hydration water to this new class of proteins. We anticipate that water is even more essential in controlling the conformational ensemble and dynamics of intrinsically disordered proteins with their large solvent-exposed surface than it is the acknowledged case for folded proteins. Specific results on the intrinsically disordered human protein tau (involved in Alzheimer disease) will help to develop a better understanding of its function and malfunction, as well as providing the basic physical understanding that may be used in drug design and pharmacological applications. The study of protein-polymer hybrids in the absence of water and solvent (second objective of our project) will provide for the first time a description of the specific protein dynamics that allow polymer-coated proteins to be biologically active despite the absence of water. describing the biologically-relevant dynamics of proteins coated with polymers will pave the way for widespread use of those hybrids in the food and pharmaceutical industries.