Using deep-cavity cavitands to study supramolecular chemistry in water

描述(由申请者提供)：本研究项目的目标是促进《科学》杂志对疏水效应的理解。水是生命的溶剂，对蛋白质和其他生物分子的结构和组装有着深远的影响，但关于这种疏水效应的作用方式仍有许多未知之处。例如，我们对霍夫迈斯特效应的理解很少--为什么一些盐(高渗)降低了有机溶质的溶解度，而另一些(杂色)则增加了溶解度--尽管这一现象是由霍夫迈斯特在120多年前首次描述的。在研究疏水效应驱动的主客体复合体的形成过程中，我们观察到络合强度随共溶质盐的变化而变化，其方式与盐诱导蛋白质沉淀或增溶的能力平行。因此，恒温饱和水溶液明显降低了主客体对的溶解度，并导致了结合亲和力的增强，而杂色体系则具有相反的作用。结合使用恒温滴定量热法(ITC)和核磁共振(核磁共振)光谱，我们追踪了杂波减弱结合的能力，这是因为阴离子对疏水凹陷具有令人惊讶的强大亲和力。换句话说，主体和客体之间的亲和力降低是因为杂化阴离子与疏水客体竞争结合到主体上。这是第一次观察到阴离子与疏水凹陷结合。此外，ITC和核磁共振光谱可以准确地确定主-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，阴离子与凹陷的结合是观察到杂交体破坏蛋白质四级和三级结构形成熔融球状状态的主要驱动力之一。为了建立在这个想法的基础上，这个方案描述了探索有机客体与一系列空穴和主体1：1络合热力学的实验。这些研究将利用ITC、核磁共振、光谱学、电子工作和X射线结晶学的组合来研究共溶质盐如何影响这些结合事件。这些数据将被用来在分子水平上建立第一个Hofmeister效应的热力学模型，并有可能统一现有的基于整体性质的Hofmeister效应模型，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.