Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 45

Fig. 14 Hosts for quaternary ammonium ions based on N -benzylated Trp residues

Fig. 15 A host based on Trp derivative indole-3-propionic acid binds quaternary ammonium ions
in buffered water

simplicity and lack of pre-organized binding pocket, host 37 binds quaternary
ammonium ions like Me 4 N + , AcCh, and Kme3 in buffered water, with two- to
fivefold selectivity over some analogous primary and secondary ammonium ions. In
this case, however, studies that extended to examination of more hydrophobic
cations showed more dramatic increases in affinity, including a 800-fold higher

affinity for Bu 4 N + than Me 4 N + . This difference is completely absent in CDCl 3
(where in fact, Bu 4 N + is not bound at all), demonstrating that it must be largely
driven by the hydrophobic effect and not by specific weak interactions between host
37 and Bu 4 N + . This lesson—that hydrophobicity can cooperate with cation-pi
interactions in aqueous medium—likely extends to naturally occurring aromatic
cages that can recognize peptides bearing quaternary trimethyllysine side chains
over their unmethylated congeners. As previously stated, the observation that a
substrate bearing neutral -C(Me) 3 side chains (32) binds more weakly to an
aromatic cage protein than does the natural partner (31) bearing -N(Me) 3 + side
chains demonstrates the importance of the cation-pi interaction. But the compari-
son of the methylated peptide 29 to its unmethylated analog 28 raises a question: all
other things being equal, the strength of the cation-pi between the aromatic cage
protein and unmethylated 28 should be stronger, because the cation is more
compact (and charge dense) and can form shorter cation-pi contacts. But of course,

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