Membrane Protein Structural Dynamics Consortium

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DESCRIPTION (provided by applicant): Membrane proteins play an essential role in controlling the movement of material and information in and out of the cell, in determining the flow and use of energy, as well as in triggering the initiation of numerous signaling pathways. To fulfill these roles, conformational and interaction dynamics exert a dominant influence on their functional behavior, for it is the interplay between structure and dynamics what ultimately defines their function. The Membrane Protein Structural Dynamics Consortium (MPSDC) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, dynamics and function in a variety of membrane proteins. The MMPSD will be organized around multidisciplinary project teams formed by investigators from 14 institutions in five different countries. These teams will study major mechanistic questions associated with membrane protein function as it relates to two major areas: energy transduction in signaling (ion channels and receptors) and energy inter-conversion (transporters and pumps). Ultimately, our goal is to decode the general mechanistic principles that govern protein movement and its associated fluctuation dynamics by dissecting and analyzing the molecular and dynamical bases of these functions at an unprecedented and quantitative level, as well as exploiting this information to engineer altered and novel activities into membrane protein frameworks to rationally evolve new functions. To accomplish its goals, the MPSDC will develop in parallel a set of tools, concepts and reagents to: 1) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence, 2D-IR) to follow conformational changes and dynamics of the determined structures; 2) Correlate dynamic measurements with high-resolution ensemble and single molecule functional measurements; and 3) Design and implement novel computational approaches to link static and dynamic data with function. Six core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will act as both, "innovation incubators" and research support centers by providing service and expertise In these critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a variety of binders and other crystallization chaperones and other target binders, the development of common computational tools to interpret and integrate the wealth of experimental data, the generation of novel, highly specific synthetic toxins and the continuous discovery of novel targets through the use of metagenomics tools.