Membrane Protein Structural Dynamics Consortium

 描述(申请人提供)：要理解膜蛋白质，人们最终必须能够可视化这些复杂的纳米尺度的“分子机器”如何在执行其功能时一个原子一个原子地移动和改变它们的形状。基于对膜蛋白是动态实体的理解，膜蛋白进化为执行一系列复杂的运动来执行其功能，因此迫切需要一部捕捉基本结构重排功能的“概念性电影”。尽管最近取得了进展，但任何特定的方法，无论是实验上的还是计算上的，都过于有限，无法提供与这种构象转变相关的瞬时特征的完整信息。要取得重大飞跃，膜蛋白动力学的定量研究需要协同和多学科的努力。这个为期10年的联盟的主要任务是定量地解决这些问题，并提供一套基本的机制原理，这些原理基于一组膜蛋白“原型”，将膜蛋白结构动力学与其功能联系起来。在这项提案中，我们重点介绍了我们在膜蛋白结晶、光谱、生物物理和建模技术方面的最新进展。通过高度协作的伙伴关系，平衡技术孵化器(科学核心)与特定项目(桥梁和试点项目)，我们已经达到了适用于复杂项目的水平 就在十年前，这些系统是不可想象的。然而，必须定量地确定动态信息才能理解功能，这需要应用已知的策略和方法来开发。我们的主张仍然是，需要结构方法、光谱技术、功能分析和计算方法之间的紧密结合，以提供对这些纳米机器及其生物学角色的深入理解。在它的第二阶段，我们发现自己处于一个极好的位置，可以扩大正在研究的系统的数量，它们的总体复杂性，并纳入新的实验和计算技术。因此，MPSDC将继续围绕多学科项目团队组织，研究与九个原型系统中的膜蛋白功能相关的主要机制问题，跨越多种能量转导机制。此外，第二阶段已到位的研究基础设施将扩大该联盟的能力，以作出进一步的转变贡献，这将确定下一个十年管理膜蛋白功能的基本原则。

 DESCRIPTION (provided by applicant): 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