Using deep-cavity cavitands to study supramolecular chemistry in water

描述（由申请人提供）：本研究计划的目标是促进科学对疏水效应的理解。水，“生命的溶剂”对蛋白质和其他生物分子的结构和组装有着深远的影响，但关于疏水效应的工作方式仍然有许多未知数。例如，我们对霍夫迈斯特效应的理解-为什么一些盐（kosmotropes）会降低有机溶质的溶解度，而另一些盐（离液剂）会增加溶解度-了解甚少;尽管霍夫迈斯特在120多年前首次描述了这种现象。 在研究由疏水效应驱动的主客体复合物的形成时，我们观察到复合的强度作为共溶质盐的函数而变化，其方式与盐诱导蛋白质沉淀或溶解的能力平行。因此，亲液性饱和剂引起主客体对的溶解度明显降低，并导致结合亲和力增强，而离液剂具有相反的效果。使用等温滴定量热法（ITC）和核磁共振（NMR）光谱的组合，我们已经追踪了离液剂的能力，以削弱结合的事实，阴离子有一个令人惊讶的强亲和力的疏水性疏水性。换句话说，主体和客体之间的亲和力降低是因为离液阴离子与疏水客体竞争结合主体。这是首次观察到阴离子结合到疏水性的疏水性基团上。此外，ITC和NMR光谱允许准确测定主-客体和主-阴离子结合的热力学。因此，我们正在收集的数据使我们能够建立霍夫迈斯特效应的第一个分子尺度模型。 这项研究计划背后的主要假设是，阴离子结合到蛋白质中是观察到离液剂破坏蛋白质四级和三级结构以形成熔融球状态的主要驱动力之一。为了建立在这个想法上，这个建议描述了实验来探测有机客体与一系列空穴主体的1：1络合的热力学。这些研究将利用ITC，NMR，光谱学，计算机工作和X射线晶体学的组合，以检查共溶质盐如何影响这些结合事件。这些数据将用于建立Hofmeister效应在分子水平上的第一个热力学模型，并有可能统一目前的Hofmeister效应模型的基础上，如溶解度，粘度和表面张力。

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.