International Collaboration in Chemistry: Aqueous Host-Guest Chemistry with Self-Assembling Metal-templated Cages

我们建议将联合收割机理论建模与协同实验合成和表征相结合，以评估影响自组装金属模板笼内小到中等大小的有机分子在水溶液主客体化学中的结合和识别的基本因素。通过利用建模和实验之间的螺旋反馈，我们希望确定关键的空间和静电相互作用，控制这将有助于合理设计改进的主客体组合。由此产生的知识将揭示当前感兴趣的各种不同问题，从蛋白质如何在其空洞内结合底物，到新的催化转化如何在有目的设计的宿主中进行。将采用基于量子力学和分子力学的理论模型。量子力学模型将通过对现有实验结构数据的验证来选择，然后部分用于为经典机械力场的选择提供进一步的基准数据。量子力学模型也将用于计算光谱数据（例如，NMR和UV/维斯），以便与晶体结构不可用的实验主体-客体组合进行比较。经典的机械力场模型将被用来模拟主客体组合的动力学行为，并预测与水结合事件相关的平均力的潜力。有了足够的验证数据，接下来将进行计算机设计工作，目标是将合成工作集中在显示增强的选择性和结合效率的主客体组合上。国际合作对于实现这一提议的目标至关重要，因为合成和光谱表征方面的专业知识集中在剑桥小组，而静态和动态建模方面的专业知识集中在明尼苏达小组。实验室之间交换研究生和博士后人员将确保初级人员接受补充实验和理论技术方面的培训，并将使他们有机会体验科学事业的国际方面。

We propose to combine theoretical modeling with collaborative experimental synthesis and characterization in order to assess the fundamental factors affecting binding and recognition in the aqueous host-guest chemistry of small to moderate-sized organic molecules inside self-assembling metal-templated cages. By taking advantage of spiral feedback between modeling and experiment, we expect to identify key steric and electrostatic interactions, the control of which will facilitate rational design of improved host-guest combinations. The knowledge thus created will shed light upon a variety of different questions of current interest, from how proteins bind substrates within their hollows, to how new catalytic transformations might be carried out within purposefully-designed hosts. Theoretical models based on both quantum and molecular mechanics will be employed. Quantum mechanical models will be chosen by validation against available experimental structural data, and then employed in part to provide further benchmark data for the selection of classical mechanical force fields. Quantum mechanical models will also be used to compute spectral data (e.g., NMR and UV/Vis) in order to compare to experimental host-guest combinations where crystal structures are not available. Classical mechanical force field modeling will be used to simulate the dynamical behavior of host-guest combinations and for the prediction of potentials of mean force associated with aqueous binding events. With sufficient validating data in hand, in silico design efforts will next be undertaken with the goal of focusing synthetic efforts on host-guest combinations showing enhanced selectivity and binding efficiencies. International collaboration is critical to achieving the goals of this proposal, as expertise in synthesis and spectroscopic characterization is concentrated in the Cambridge group while expertise in static and dynamic modeling is concentrated in the Minnesota group. Exchange of graduate student and postdoctoral personnel between laboratories will ensure that junior personnel receive training in complementary experimental and theoretical techniques, and will also afford them opportunities to experience international aspects of the scientific enterprise.