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

我们建议将理论模拟与协同实验合成和表征相结合，以评估在自组装金属模板笼子内中小尺寸有机分子的水相主客体化学中影响结合和识别的基本因素。通过利用模型和实验之间的螺旋反馈，我们有望识别关键的空间和静电相互作用，对其进行控制将有助于改进的主客体组合的合理设计。这样创造的知识将阐明当前感兴趣的各种不同的问题，从蛋白质如何在其空洞中结合底物，到如何在有目的地设计的宿主中进行新的催化转化。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照现有的实验结构数据进行验证来选择，然后在一定程度上用于为选择经典机械力场提供进一步的基准数据。量子力学模型也将被用来计算光谱数据(例如，核磁共振和UV/Vis)，以便与晶体结构不可用的实验主客体组合进行比较。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，并用于预测与水结合事件相关的平均力势。有了足够的验证数据，接下来将在电子设计方面进行努力，目标是将合成努力集中在显示更高的选择性和结合效率的主-客体组合上。国际合作对实现本提案的目标至关重要，因为合成和光谱表征方面的专业知识集中在剑桥集团，而静态和动态建模的专业知识集中在明尼苏达集团。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的培训，并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.