Optimization of a synthetic arginine receptor. Systematic tuning of noncovalent interactions

The simple arginine binder 1 could be optimized by strengthening pi-cation as well as electrostatic interactions. Electron-donating or -withdrawing substituents in the 5-position provide experimental evidence for pi-cation interactions, because binding energies increase by up to 0.6 kcal/mol due to a single benzene-guanidinium interaction. Even more effective is the introduction of a third phosphonate functionality at the correct distance, so that the guanidinium cation is recognized by optimal electrostatic and hydrogen bond interactions. Monte Carlo simulations and NOESY experiments confirm the expected complex geometries. The optimized host molecule 8 binds arginine half an order of magnitude more efficiently than the parent molecule.