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 Midwest Center for Membrane Protein Structural Dynamics (MMPSD) is proposed as a highly interactive, tightly integrated and multidisciplinary effort focused on elucidating the relationship between structure, free energy landscapes, dynamics and function.

The MMPSD will be organized around multidisciplinary project teams with investigators from institutions clustered geographically inn [sic] the Midwest to maximize true interactive collaborations and an efficient exchange of ideas. These teams will study major mechanistic questions associated with membrane protein function as it relates to three major areas: energy transduction in signaling (ion channels and receptors) energy interconversion (transporters and pumps) and chemo-transduction pathways (membrane-embedded proteases and phosphatases). Our ultimate goals 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 MMPSD will develop in parallel a set of tools, concepts and reagents to: 1) Determine time-averaged structures of "Archetype" membrane proteins using Chaperone-assisted crystallization methods; 2) Apply state of the art spectroscopic methods (Magnetic Resonance, Fluorescence) to follow conformational changes and dynamics of the determined structures; and 3) Design and implement novel computational approaches to link static and dynamic data with function. Four core facilities will feed and interconnect with the individual projects in a highly interactive way. The cores will support the research in the Center by providing service and expertise in four critical areas: Membrane protein expression, the establishment of chemical synthesis capabilities for probes and detergents, the generation of a large variety of crystallization chaperones and other target binders, and generation of a pipeline of novel membrane targets through metagenomics approaches.

All of the information, tools and new reagents/targets will be shared with the research community at large through the "membrane protein dynamics gateway", a state of the art web page and a series of scientific meetings open to the public.

R24GM084757

2008-03-01

2010-02-28