Using deep-cavity cavitands to study supramolecular chemistry in water

利用深腔空配体研究水中的超分子化学

• 批准号: 8258409
• 负责人: BRUCE C GIBB
• 金额: $ 28.29万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258409
• 关键词: Affinity; Age; Anions; Binding; Biological Models; Calorimetry; Chemistry; Complex; Computer Simulation; Data; Documentation; Employee Strikes; Event; Goals; Inorganic Sulfates; Ions; Lead; Life; Modeling; Modus; Molecular; NMR Spectroscopy; Oils; Perchlorates; Precipitation; Property; Proteins; Research; Salts; Science; Series; Shapes; Sodium Chloride; Solubility; Solutions; Solvents; Structure; Surface Tension; Thermodynamics; Titrations; Unspecified or Sulfate Ion Sulfates; Viscosity; Water; Work; X-Ray Crystallography; aqueous; base; cavitand; driving force; mathematical model; molecular scale; programs; protein structure; research study; solute

DESCRIPTION (provided by applicant): The goal of this program of research is to contribute to Science's understanding of the Hydrophobic Effect. Water, the 'solvent of life' has a profound influence on the structure and assembly of proteins and other biomolecules, yet there are still many unknowns regarding the modus operandi of the Hydrophobic Effect. For example, our understanding of the Hofmeister Effect - why some salts (kosmotropes) decrease the solubility of organic solutes whilst others (chaotropes) increase solubility - is poorly understood; even though the phenomenon was first described by Hofmeister over 120 years ago. In studying the formation of a host-guest complex driven by the hydrophobic effect, we have observed that the strength of complexation varies as a function of co-solute salts, in a manner paralleling the ability of salts to induce either precipitation or solubilization of proteins. Thus, kosmotropic sats cause an apparent decrease in the solubility of the host-guest pair and lead to an enhancement of the binding affinity, whilst chaotropes have the opposite effect. Using a combination of Isothermal Titration Calorimetry (ITC) and Nuclear Magnetic Resonance (NMR) spectroscopy, we have traced the ability of chaotropes to weaken binding to the fact that anions have a surprisingly strong affinity for hydrophobic concavity. In other words, the reduced affinity between host and guest occurs because chaotropic anions compete with the hydrophobic guest for binding to the host. This is the first observation of anions binding to hydrophobic concavity. Furthermore, ITC and NMR spectroscopy allows the accurate determination of the thermodynamics of host-guest and host-anion binding. As a result, the data we are gathering is allowing us to build the first molecular-scale models of the Hofmeister Effect. The major hypothesis behind this program of study is that anion binding to concavity is one of the major driving forces behind the observation that chaotropes break up protein quaternary and tertiary structure to form the molten-globule state. To build on this idea, this proposal describes experiments to probe the thermodynamics of 1:1 complexation of organic guests to a series of cavitand hosts. These studies will utilize a combination of ITC, NMR, spectroscopy, in silico work, and X-ray crystallography, to examine how co solutes salts influence these binding events. This data will be used to build the first thermodynamic models of the Hofmeister Effect at the molecular level, and has the potential to unify current models of the Hofmeister Effect based on bulk properties such as solubility, viscosity, and surface tension. PUBLIC HEALTH RELEVANCE: The Hydrophobic Effect, the phenomenon best illustrated by the age-old adage that oil and water don't mix, is responsible for the structure of proteins and indeed most biomolecules. However, there are many facets of the Hydrophobic Effect, and how salts present in solution modulate it, which are poorly understood. The studies in this proposal will reveal new information about the Hydrophobic Effect, and will prove of utility to a broad range of biosciences.

描述（由申请人提供）：该研究计划的目的是为科学对疏水作用的理解做出贡献。水，“生命的溶剂”对蛋白质和其他生物分子的结构和组装有深远的影响，但是关于疏水作用的作案手法仍然有许多未知数。例如，我们对Hofmeister效应的理解 - 为什么有些盐（kosmotropes）降低了有机溶质的溶解度，而其他盐（Chaotropes）会增加溶解度 - 知之甚少；即使这种现象是由霍夫梅斯特（Hofmeister）在120年前首次描述的。 在研究由疏水效应驱动的宿主 - 晶体复合物的形成时，我们观察到，络合强度随着共糖盐的函数而变化，与盐诱导蛋白质降水或溶解的能力相似。因此，Kosmotropic SATS导致宿主 - 阵阵对的溶解度明显降低，并导致结合亲和力的增强，而Chaotropes具有相反的效果。使用等温滴定量热法（ITC）和核磁共振（NMR）光谱法，我们追溯了Chaotropes削弱结合的能力，即阴离子具有令人惊讶的疏水性亲和力。换句话说，宿主和客人之间的亲和力减少是因为混乱的阴离子与疏水嘉宾竞争与宿主结合。这是阴离子与疏水凹陷结合的首次观察。此外，ITC和NMR光谱允许准确地测定宿主 - 吉斯特和宿主 - 胺结合的热力学。结果，我们收集的数据使我们能够构建HofMeister效应的第一个分子规模模型。 该研究程序背后的主要假设是，阴离子与凹面的结合是观察到的混合体破坏蛋白质季季和第三纪结构以形成熔融细胞状态的主要驱动力之一。为了基于这个想法，该建议描述了实验，以探测有机客人络合1：1与一系列cavitand宿主的热力学。这些研究将利用ITC，NMR，光谱，在计算机工作和X射线晶体学中的组合来检查CO溶液如何影响这些结合事件。这些数据将用于在分子水平上构建HOFMEISTER效应的第一个热力学模型，并有可能基于溶解度，粘度和表面张力来统一HofMeister效应的当前模型。 公共卫生相关性：疏水作用是石油和水不混合的古老的格言最能说明的现象，是蛋白质乃至大多数生物分子的结构。但是，疏水作用有许多方面，以及溶液中存在的盐如何调节它的理解不足。该提案中的研究将揭示有关疏水作用的新信息，并将证明对广泛的生物科学的实用性。