Dynamics and Mechanism of Water-Protein Interactions

水-蛋白质相互作用的动力学和机制

• 批准号: 8186042
• 负责人: DONGPING ZHONG
• 金额: $ 28.98万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8186042
• 关键词: Active Sites; Address; Amino Acids; Architecture; Benchmarking; Binding; Binding Sites; Biological Process; Catalysis; Chemical Structure; Chemicals; Complex; Coupled; Coupling; DNA; DNA-Directed DNA Polymerase; Data; Docking; Drug Design; Enzymes; Evolution; Future; Goals; Heterogeneity; Hydration status; Investigation; Isotopes; Knowledge; Lasers; Lead; Life; Maps; Mediation; Membrane Proteins; Methodology; Methods; Modeling; Molecular; Motion; Mutation; Nature; Neurodegenerative Disorders; Optics; Prevention; Property; Protein Dynamics; Protein Engineering; Proteins; Relaxation; Research; Resolution; Role; Scanning; Science; Series; Site-Directed Mutagenesis; Spectrum Analysis; Structural Protein; Structure; Surface; System; Temperature; Time; Tryptophan; Water; biological systems; flexibility; globular protein; improved; insight; interfacial; molecular dynamics; molecular recognition; mutant; novel; practical application; protein aggregation; protein protein interaction; protein structure; simulation

DESCRIPTION (provided by applicant): Protein hydration is a long-standing and unresolved problem in protein science and water-protein interactions/dynamics are essential to a protein's structure, dynamics and function. The elucidation of such coupling motions at the molecular level not only has fundamental significance in understanding protein stability and flexibility, folding, misfolding and aggregation, recognition and binding, and enzyme catalysis, but also has a significant impact on practical applications such as drug design. Various methods and strategies have been used to characterize water motions around proteins, but such studies have been challenging and difficult because the dynamics are ultrafast and heterogeneous. A general molecular picture has not been obtained yet. We have recently developed a methodology by integrating state-of-the-art femtosecond laser spectroscopy and site-directed mutagenesis and have reached femtosecond temporal resolution and single-residue spatial resolution. Using intrinsic amino acid tryptophan as a local optical probe, we have recently mapped out the global water motions around an a-helical globular protein with unprecedented details. In this proposal, we will systematically characterize water motions around small structural motifs, on surfaces of ¿-sheet globular proteins, and at interfaces of protein-DNA complexes. Specifically, Aim 1 is to elucidate the hydration dynamics evolution by systematic characterization of water motions from an a-helix, to a ¿-hairpin, to a small cage, and to a mini-protein. With the fundamental understanding of water motions around these elemental structure units, in Aim 2 we extend to characterize the global surface hydration dynamics around two ¿-sheet globular proteins. Combined with recently characterized water dynamics around the a-helical globular protein, we hope that such systematic comparisons will reveal the different dynamic nature of water motions around different protein architectures with different size, rigidity, chemical identity. Finally, in Aim 3, we investigate the interfacial hydration dynamics by systematic characterization of water motions at the interfaces of two protein-DNA complexes to address the dynamic role of water motions in mediation of protein-DNA recognition. The new knowledge obtained from these systematic investigations is fundamental to a wide variety of biological processes and also significant to a series of practical applications. PUBLIC HEALTH RELEVANCE: Water is an active matrix of life and water-protein interactions are essential to protein structure, dynamics and function. Here we develop a novel method with femtosecond temporal resolution and single-residue spatial resolution to systematically characterize water motions around protein surfaces/interfaces and thus reveal the molecular mechanism of water-protein interactions. The new knowledge from these studies is fundamental to a wide variety of biological processes such as molecular recognition and enzyme catalysis and also significant to a series of practical applications such as drug design and prevention of protein aggregation to neurodegenerative diseases.

描述（由申请人提供）：蛋白质水合是蛋白质科学中长期存在且未解决的问题，水-蛋白质相互作用/动力学对于蛋白质的结构、动力学和功能至关重要，不仅在分子水平上阐明这种耦合运动。对于理解蛋白质的稳定性和灵活性、折叠、错误折叠和聚集、识别和结合以及酶催化具有根本意义，而且对药物设计等实际应用中的各种方法和策略也具有重大影响。已被用来表征蛋白质周围的水运动，但此类研究具有挑战性且困难，因为动力学是超快且异质的，我们最近通过整合最新技术开发了一种方法。利用飞秒激光光谱和定点诱变，我们已经达到了飞秒时间分辨率和单残基空间分辨率，利用内在氨基酸色氨酸作为局部光学探针，我们最近绘制了围绕一个区域的全球水运动。具有前所未有的细节的α-螺旋球状蛋白在本提案中，我们将系统地表征 ¿ 表面上小结构图案周围的水运动。具体而言，目标 1 是通过系统表征从 a 螺旋到 ¿ 的水运动来阐明水合动力学演化。 -发夹、小笼子和迷你蛋白质 通过对这些基本结构单元周围的水运动的基本了解，在目标 2 中，我们扩展了围绕两个 ¿ 的全局表面水化动力学的特征。结合最近表征的α-螺旋球状蛋白周围的水动力学，我们希望这种系统比较能够揭示具有不同大小、刚性和化学特性的不同蛋白质结构周围的水运动的不同动态性质。目标 3，我们通过系统表征两个蛋白质-DNA 复合物界面处的水运动来研究界面水化动力学，以解决水运动在介导蛋白质-DNA 识别中的动态作用。这些系统研究是多种生物过程的基础，对一系列实际应用也具有重要意义。 公共健康相关性：水是生命的活性基质，水与蛋白质的相互作用对于蛋白质的结构、动力学和功能至关重要。在这里，我们开发了一种具有飞秒时间分辨率和单残留空间分辨率的新方法，可以系统地表征蛋白质表面周围的水运动。 /界面，从而揭示水-蛋白质相互作用的分子机制，这些研究的新知识是分子识别和酶催化等多种生物过程的基础，对药物设计和药物设计等一系列实际应用也具有重要意义。预防蛋白质聚集导致神经退行性疾病。