Membrane Protein Structural Dynamics Consortium

 描述（由申请人提供）：为了了解膜蛋白，人们必须最终能够可视化这些复杂的纳米级“分子机器”如何在执行其功能时作为时间的函数逐个原子地移动和改变其形状。基于膜蛋白是动态实体的理解，进化执行复杂的运动来执行其功能，迫切需要的是一个“概念电影”，捕捉基本的结构重排功能。尽管最近的进展，任何特定的方法，尽管实验或计算，是太有限，提供完整的信息与这种构象转变的瞬态功能。为了取得重大飞跃，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械原理，这些原理基于一套膜蛋白“原型”将膜蛋白结构动力学与其功能联系起来。在这个建议中，我们强调了我们最近在膜蛋白结晶，光谱，生物物理和建模技术的进展。通过高度合作的伙伴关系，平衡技术孵化器（科学核心）与具体项目（桥接和试点项目），我们已经达到了一个复杂的适用性水平。 十年前无法想象的系统。然而，必须定量地确定动态信息以理解功能，这需要应用已知的策略和方法开发。我们的主张仍然是结构方法，光谱技术，功能分析和计算方法之间的紧密结合，需要提供这些纳米机器及其生物学作用的深入了解。 在其第二阶段，我们发现自己处于一个非常有利的位置，以扩大正在研究的系统的数量，它们的整体复杂性，并结合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9个原型系统中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，为第二阶段建立的研究基础设施将扩大该联合会的能力，使其能够作出进一步的变革性贡献，这些贡献将确定下一个十年中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