High Fidelity Kinetic Self-Sorting in Multi-Component Systems Based on Guests with Multiple Binding Epitopes

The molecular recognition platforms of natural systems often possess multiple binding epitopes,
each of which has programmed functional consequences. We report the dynamic behavior of a system
comprising CB[6], CB[7], and guests cyclohexanediammonium (1) and adamantanealkylammonium (2)
that we refer to as a two-faced guest because it contains two distinct binding epitopes. We find that the
presence of the two-faced guestjust as is observed for protein targeting in vivodictates the kinetic pathway
that the system follows toward equilibrium. The influence of two-faced guest structure, cation concentration,
cation identity, and individual rate and equilibrium constants on the behavior of the system was explored
by a combination of experiment and simulation. Deconstruction of this system led to the discovery of an
anomalous host−guest complex (CB[6]·1) whose dissociation rate constant (kout = 8.5 × 10-10 s-1) is
≈100-fold slower than the widely used avidin·biotin affinity pair. This result, in combination with the analysis
of previous systems which uncovered extraordinarily tight binding events (Ka ≥ 1012 M-1), highlights the
inherent potential of pursuing a systems approach toward supramolecular chemistry.