To understand membrane proteins, one must ultimately be able to visualize how these complex nanoscale molecular machines move and change their shape atom-by-atom as a function of time while they perform their function. Grounded on the understanding that membrane proteins are dynamic entities that evolved to execute complex sets of movements to perform their functions, what is critically needed is a conceptual movie that captures the essential structural rearrangements underlying function. In spite of recent progress, any particular approach, albeit experimental or computational, is too limited to provide complete information about the transient features associated with such conformational transitions. To make a significant leap forward, the quantitative study of membrane protein dynamics requires a synergistic and multi-disciplinary effort. The main task of this 10-year Consortium is to quantitatively address these issues and provide a basic set of mechanistic principles that relate membrane protein structural dynamics to their function based on a set of membrane protein archetypes. In this proposal, we highlight our recent advances in membrane protein crystallization, spectroscopic, biophysical and modeling techniques. Through highly collaborative partnerships that balance technology incubators (the scientific Cores) with specific projects (Bridging and Pilot projects) we have reached a level of applicability to complex systems unimaginable just a decade ago. However, dynamic information must be quantitatively determined to understand function and this requires the application of both known strategies and methods development. Our proposition remains that a tight integration between structural methods, spectroscopic techniques, functional analyses and computational approaches, is required to provide a deep understanding of these nano-machines and their biological roles. In its Phase II, we find ourselves in an excellent position to expand the number of systems under study, their overall complexity and incorporate new experimental and computational techniques. Accordingly, the MPSDC will continue to be organized around multidisciplinary project teams studying major mechanistic questions associated with membrane protein function in nine archetype systems, spanning a multiplicity of energy transduction mechanisms. Furthermore, the research infrastructure in place for phase II will extend the capacity of the Consortium to make further transforming contributions that should define the fundamental principles governing membrane protein function into the next decade
The interplay between structure and molecular dynamics is what ultimately defines a biological system's function. This project seeks to gain knowledge of how these fundamental phenomena influence the way membrane proteins function as they work to control the movement of molecules and signals in and out of our cells. Such information will be required to understand both the complex web of signaling and energy transduction mechanisms required for normal cellular function and their pathologies.
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