Achieving High Affinity and Selectivity for Asymmetric Dimethylarginine by Putting a Lid on a Box

Abstract

The methylation states of Lysa nd Arg represent aparticularly challenging set of targets to distinguish selectively in water using synthetic receptors.T od ate,t rimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lysand Arg that can be recognized selectively.H ere,w er eport the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using ab iased dynamic combinatorial chemistry (DCC) library to generate ar eceptor mimicking the 5-sided box-like shape of Rme2 reader proteins,afeature that has been hypothesized to impart selectivity.A dditionally,w es ynthesized at hioether-linked analogue of the resulting receptor to provide an ovel scaffold with maintained selectivity but greater stability.T his work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.

Mimicking Biological Recognition: Lessons in Binding Hydrophilic Guests in Water

“…Turning again to native reader proteins for inspiration, Mullins, Waters, and co‐workers hypothesized that the A 2 X receptors previously reported did not exhibit selectivity for methylated states of arginine because they are spherical in shape, much like the binding pockets of reader proteins for Kme3 [128] . Reader proteins that bind methylated states of arginine, however, have box‐shaped pockets with a narrower cleft that can accommodate methylated Arg but not methylated Lys .…”

Molecular Recognition Mediated by Hydrogen Bonding in Aqueous Media

“…Arginine methylation is a post‐translational modification with relevance to a number of diseases. Although the binding sites employed are largely apolar, H‐bonding to unmodified NH appears to play a role in some cases [46] …”

Molecular Recognition Mediated by Hydrogen Bonding in Aqueous Media

“…More recently the Waters group have investigated the binding of N-methylated arginine side-chains using receptors obtained via dynamic combinatorial chemistry.A rginine methylation is ap osttranslational modification with relevance to an umber of diseases.A lthough the binding sites employed are largely apolar, H-bonding to unmodified NH appears to play arole in some cases. [46] Cucurbiturils can also bind selectively to peptides.G iven their hydrophobic interiors these toroidal structures might be expected to target aromatic side chains as in phenylalanine and tryptophan. Working with cucurbit [8]uril (CB8,c f. Figure 13) the group of Urbach showed that this is indeed the case.…”