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

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.

Who will benefit from this research?

The immediate beneficiaries will be the PhD student and PDRA. Other direct beneficiaries will include researchers from the multidisciplinary training programmes that the Nitschke group takes part in, such as the Nanosciences Doctoral Training Programme, the Cancer Research UK MedChem Programme, and the CamBridgeSENS multidisciplinary network on sensor technology. Other academic groups as well as industrial scientists interested in host-guest chemistry, physical organic chemistry, sensors, and supramolecular systems will also be able to benefit from this work and build upon it in new directions. Other users and beneficiaries of this research will be from outside of the academic/industrial research community, for example the media, publication, and the general public.

How will they benefit from this research?
Research: Due to the multidisciplinary nature of the project, consultations with other experts within the department, the UK and worldwide are expected. The communication would encourage further understanding and investigation of chemistry and technology, which would generate scientific benefit to the University and other researchers worldwide. Our association with the Cambridge EPSRC-funded Nano-DTC can serve as a vector to allow the rules governing host-guest binding of the cages that we will prepare to be expanded to other host-guest systems very rapidly.
Industry: A solid understanding of the rules governing host-guest chemistry is key in the development of host-guest systems in applications such as enzymatic catalysis. Clearly, any input into the field of catalysis research - the basis for one of the largest manufacturing industries in the UK - would be beneficial, for example for the fine chemicals industries.
General public: In addition to the increase in wealth associated with technological progress, the public stands to benefit from synergies between the research proposed herein and an ongoing project in the group that is carried out under the auspices of the Home Office - Counter Terrorism and Intelligence Directorate, in which other cage compounds are projected to trap and render harmless chemical warfare agents. Helping keep the UK safe from rogue CWA release is clearly of vital importance.

What will be done to ensure that they benefit from this research?
Industry: We have entered into discussion with Cambridge Enterprise, the University's technology transfer office, regarding possible IP issuing from the cages that have already been prepared. We will continue these discussions, especially in the context of our UK Home Office contract involving the trapping of harmful chemical warfare agents.
General public: The group participates in the annual Cambridge Science Festival to present posters, deliver public lectures, and organise hands-on scientific activities and demonstrations. Based on our group's recent discovery, we plan to demonstrate how white phosphorous can be rendered air-stable by encapsulation during the week-long Cambridge Science Festival in March. We will use cartoon schemes to help introduce the general public to the basic concepts of supramolecular chemistry - an area of chemistry whose aesthetic appeal can readily be appreciated by the general public - thus helping to inspire young people to devote themselves to scientific research.