Structure-Dynamics Relationships in Proteins: A multi-faceted characterizati

蛋白质的结构-动力学关系：多方面的表征

• 批准号: 8149798
• 负责人: MATTHIAS BUCK
• 金额: $ 29.53万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8149798
• 关键词: Address; Affect; Binding; Biophysics; Cells; Communication; Complex; Core Protein; Coupling; Data; Data Set; Development; Diagnostic; Distant; Docking; Drug Design; Event; Generations; Guanosine Triphosphate Phosphohydrolases; Information Theory; Investigation; Joints; Ligands; Link; Malignant Neoplasms; Measurement; Methods; Modeling; Motion; Neoplasm Metastasis; Play; Protein Dynamics; Protein Region; Proteins; Protocols documentation; Relaxation; Role; Sampling; Signal Transduction; Signaling Protein; Site; Solutions; Solvents; Structural Protein; Structure; Surface; Testing; Therapeutic Agents; Time; Ubiquitin; Validation; Viscosity; base; combat; conformer; design; feeding; improved; insight; methyl group; molecular dynamics; mutant; next generation; plexin; programs; protein complex; protein function; protein structure; protein structure function; public health relevance; research study; restraint; simulation; structural biology; tumorigenesis

DESCRIPTION (provided by applicant): Structure - Dynamics Relationships in Proteins: Multi-faceted characterization of structure and its fluctuations by NMR relaxation measurements and molecular dynamics simulations. Protein fluctuations and their relationship to protein structure and function continue to challenge biophysical measurements and simulations. All three aspects of proteins (dynamics, structure and function) are intimately linked. Recently it has become clear that alterations in protein dynamics alone can be used to communicate between distant sites in proteins. The structures and fluctuations that are involved in such communication conduits (and the coupling between them) are not yet well understood. We address several aspects of the structure-dynamics relationship. Aim 1: In a joint NMR experimental -computational refinement approach we seek to improve the representation of ps-ns timescale dynamics in protein structural ensembles. A statistical and an information theory based approach will be employed to evaluate the experimental restraints and the number of local conformers to be used in the structure refinement. The results will be compared to unrestrained molecular dynamics simulations and to order parameters derived from NMR relaxation measurements. The structural ensembles will be useful for ligand and protein docking calculations in drug design. Aim 2: Our study seeks to reveal design principles that allow a coupling between protein loops and the fluctuations of core structures. Again, both solution NMR experimental and computational strategies will be combined for several proteins, including for ubiquitin and for the RhoGTPase binding domain of plexin-B1 (RBD), which has a ubiquitin fold with long loop insertions. The loops as well as the protein core will be manipulated in order to probe possible dynamic coupling between the two. Possible motional coupling across a protein-protein interface will also be examined for the RBD-GTPase complex. Aim 3: The possibility that the global stochastic motion of the protein can affect the local, internal dynamics will be examined using NMR relaxation at different solvent viscosities and long time-scale Langevin/Brownian dynamics simulations. Aim 4: Methods for enhanced sampling of conformational space will be tested and a next generation force field for the molecular dynamics program CHARMM/NAMD will be validated against NMR data. Overall, in this project, several computational and experimental strategies will be brought together in order to provide deep insight into the relationship between protein structures, and internal as well as global protein dynamics. Several of the proteins studied have important roles in oncogenesis and cell metastasis and their further investigation will suggest new avenues for the design of diagnostic or therapeutic agents to combat cancer. PUBLIC HEALTH RELEVANCE: The joint experimental and computational project will provide detailed insight into the interrelationship between protein structure and protein internal and global dynamics. The basic questions addressed are fundamental to the field of protein biophysics and structural biology. The results of this study will help to understand protein function, here specifically of cell signaling proteins. Several of the proteins involved play important roles in cancer development and spreading, and their further investigation will suggest new avenues for the design of diagnostic or therapeutic agents.

描述（由申请人提供）：结构-蛋白质中的动力学关系：通过核磁共振弛豫测量和分子动力学模拟对结构及其波动的多方面表征。蛋白质波动及其与蛋白质结构和功能的关系继续挑战生物物理测量和模拟。蛋白质的三个方面（动力学、结构和功能）都是密切相关的。最近已经很清楚，蛋白质动力学的改变可以单独用于蛋白质中遥远位点之间的通信。这种通信管道（以及它们之间的耦合）所涉及的结构和波动尚未得到很好的理解。我们讨论了结构-动力学关系的几个方面。目的1：在联合核磁共振实验-计算改进方法中，我们寻求改进蛋白质结构集成中ps-ns时间尺度动力学的表示。将采用基于统计和信息理论的方法来评估实验约束和用于结构改进的局部构象的数量。结果将与不受约束的分子动力学模拟和从核磁共振弛豫测量中得到的有序参数进行比较。这些结构集成将有助于药物设计中的配体和蛋白质对接计算。目的2：我们的研究旨在揭示允许蛋白环和核心结构波动之间耦合的设计原则。同样，溶液核磁共振实验和计算策略将结合几种蛋白质，包括泛素和丛状蛋白b1 （RBD）的RhoGTPase结合域，它具有泛素折叠和长环插入。为了探测两者之间可能的动态耦合，将对环以及蛋白质核心进行操作。RBD-GTPase复合体在蛋白质-蛋白质界面上可能的运动耦合也将被研究。目标3：蛋白质的全局随机运动影响局部内部动力学的可能性将通过不同溶剂粘度和长时间尺度朗格万/布朗动力学模拟的核磁共振弛豫来检验。目标4：将测试增强构象空间采样的方法，并根据核磁共振数据验证分子动力学程序CHARMM/NAMD的下一代力场。总的来说，在这个项目中，几种计算和实验策略将被结合在一起，以便深入了解蛋白质结构之间的关系，以及内部和全局蛋白质动力学。所研究的一些蛋白质在肿瘤发生和细胞转移中起着重要作用，它们的进一步研究将为设计抗癌诊断或治疗药物提供新的途径。