Seing the invisible, or, how to integrate metadynamics in the quantitative analysis of protein/protein complexes right at your fingertips. – METADYN

Molecular interactions play a key role in all the branch of analytical sciences. Among these interactions, those involving proteins are particularly fascinating as they comprise a large number of degree of freedom and are present in all biological processes. Indeed, a key feature defining protein function in living cells is their capacity to selectively interact with other molecules in their environment. Combined in diverse cellular assemblies that vary with cell cycle, tissue type and in response to external stimuli, proteins constitute the nanomachines of biology. Understanding how proteins move and interact with neighboring molecules is necessary for solving critical puzzles in molecular biology. Filling the sizeable gaps in our knowledge of protein/protein interactions and protein function (or malfunction) is increasingly crucial for the design of potential new drugs and to better understand biological processes leading to specific diseases. These opportunities can be fully exploited only if technological progress is paired with a major step forward in our understanding of the detailed physical and chemical factors regulating protein mechanisms (encompassing dynamics, folding, interactions, and assembly) and consequently in our ability to model and predict these processes. While protein/small molecules interactions are now routinely modeled by molecular dynamics to extract thermodynamical parameters, the study of protein/protein interactions at the molecular level still poses outstanding challenges both for theory and experiment. No single technique can at present span the whole range of typical time and length scales relevant for a protein biological function and interaction. Nevertheless, qualitative and quantitative analyses of these interactions is possible at microscopic and atomic resolutions using Nuclear Magnetic Resonance (NMR) with complementary biophysical methods like Isothermal Titration Calorimetry (ITC) or Small Angle X-ray/neutron scattering (SAXS/SANS). At this level, NMR is especially useful as it can probe dynamical events on a broad time scale and is highly sensitive to processes relevant to biomacromolecules, such as inter-domain motions, exchange equilibria and catalysis. In our quest to see the invisible, new theoretical and computational approaches need to be developed in order to address the current challenge. It is our belief that this goal can be achieved by reconciling biological and biochemical approaches with a physical and mathematical perspective of the problem.
Our project is located at the frontier of analytical sciences, biochemistry as well as computational science and will merge researchers of different fields. We do not propose another additional tool to derive structures guided by experimental data. Conversely, we propose to develop a novel general-purpose integrated analytical tool that combines both experimental and molecular dynamics simulation approaches for a better understanding of protein/protein interactions by modeling in the real time these interactions and binding pathways to get access to thermodynamic parameters. Far away from the dedicated national infrastructures that request a huge amount of power and cooling fluids, we propose to quantitatively study protein/protein interactions on everybody's office with an affordable price equipment and to integrate experimental data to accelerate this process. Protein/protein interactions will be right at your fingertips.