A synthetic host-guest system achieves avidin-biotin affinity by overcoming enthalpy-entropy compensation

Abstract

The molecular host cucurbit[7]uril forms an extremely stable inclusion complex with the dicationic ferrocene derivative bis(trimethylammoniomethyl)ferrocene in aqueous solution. The equilibrium association constant for this host-guest pair is 3 x 10(15) M(-1) (K(d) = 3 x 10(-16) M), equivalent to that exhibited by the avidin-biotin pair. Although purely synthetic systems with larger association constants have been reported, the present one is unique because it does not rely on polyvalency. Instead, it achieves its extreme affinity by overcoming the compensatory enthalpy-entropy relationship usually observed in supramolecular complexes. Its disproportionately low entropic cost is traced to extensive host desolvation and to the rigidity of both the host and the guest.

Fig. 1.

Chemical structures of the host cucurbit[7]uril and ferrocene guests: 1-hydroxymethylferrocene (1), 1-trimethylammoniomethylferrocene (2), and 1,1′-bis(trimethylammoniomethyl)ferrocene (3).

Fig. 2.

Competition ITC experiments on complexation of 3 with CB[7] in 73 mM solution of aminomethylcyclohexane HCl used as competitor (Curve fitting was performed by using the Single Set of Identical Sites Model).

Fig. 3.

The thermodynamic data obtained for complexation of guests 1, 2, and 3 with CB[7] (green dots), which are significantly deviated from the enthalpy–entropy compensation plot for cyclodextrin-guest complexation (black circles: data adopted from refs. and 10).

Fig. 4.

X-ray crystal structure of CB[7]·3 complex (A) and computed conformation of CB[7]·3 complex from the second-generation Mining Minima algorithm (B).