Learning from Proteins and Drugs: Receptors That Mimic Biomedically Important Binding Motifs - Designing Receptors for the Next Generation of Biosensors - page 46

Fig. 16 p- Sulfonatocalix[4]arene (38) and macrocycle 39 mimic the aromatic-rich pockets of
methyllysine-binding proteins in different ways. Both bind peptides bearing trimethyllysine side
chains in buffered water with protein-like affinities and selectivities
the unmethylated peptide 28 has a handicap, in that the primary -NH 3 + cation of
its side chain is strongly engaged with a shell of hydrating water molecules.
The affinities for these peptides with their partner protein HP1 are provided in
Fig. 13 [ 61 ]. The hydrophobic effect that is induced upon methylation is an
important player that works alongside cation-pi interactions and dispersive
interactions in generating the natural selectivities of aromatic cage proteins for
their trimethyllysine targets over unmethylated counterparts.
The calixarenes, a family of hosts that present multiple phenol rings in a
macrocyclic arrangement, have been widely explored as biomimetic hosts. A
particularly large body of work exists on sulfonated calixarenes, which are soluble
in water and capable of binding a wide variety of natural and unnatural guests
presenting ammonium ions. Hosts like p -sulfonatocalix[4]arene (38) have long
been known to bind biologically important quaternary ammonium ions like
acetylcholine [ 66 , 67 ]. More recent work has broadly explored their abilities to
bind cationic amino acids, peptides, and proteins [ 68 , 69 ]. Host 38 binds lysine,
arginine, and histidine in buffered water with affinities of 520, 330, and 20 M -1 ,
respectively (Fig. 16 )[ 70 - 72 ]. Affinities rise upon methylation, with asymmetric
dimethylarginine ( a DMA ) and symmetric dimethylarginine ( s DMA ) binding
threefold stronger than unmethylated arginine [ 72 ]. The lysine series displays
even stronger dependence on methylation state, with affinities ranging up to
37,000 M -1 for the 1:1 complexation of trimethyllysine (Kme3) and 96,600 M -1
for the short trimethyllysine-containing peptide R-(Kme3)-S-T [ 72 ]. Such high
selectivities for the quaternary ammonium ions over primary counterparts are
dramatic and consistently displayed for this host. The difference probably arises
from a change in binding mode: unmethylated lysine side chains bury their most
hydrophobic elements, the aliphatic CH 2 groups, inside of the aromatic cavity of
host 38 and leave the polar -NH 3 + group exposed to the polar sulfonate functional
groups and external solvent [ 73 ]. Trimethyllysine, instead, buries its -NMe 3 + group