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

Abstract

The methylation states of Lys and Arg represent a particularly challenging set of targets to distinguish selectively in water using synthetic receptors. To date, trimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lys and Arg that can be recognized selectively. Here, we report the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using a biased dynamic combinatorial chemistry (DCC) library to generate a receptor mimicking the 5‐sided box‐like shape of Rme2 reader proteins, a feature that has been hypothesized to impart selectivity. Additionally, we synthesized a thioether‐linked analogue of the resulting receptor to provide a novel scaffold with maintained selectivity but greater stability. This work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.

Contribution of Electrostatic CH3–π Interactions to Recognition of Histone Asymmetric Dimethylarginine by the SPIN1 Triple Tudor Domain

“…Arginine methylation (Rme) is a common post-translational modification (PTM) which occurs on all four human histones. − This PTM plays key roles in transcriptional activation or repression, depending on the site and degree of methylation on the histone tail. ,,− Three different arginine methylation states exist: monomethylarginine (Rme1), symmetric dimethylarginine (Rme2s), and asymmetric dimethylarginine (Rme2a), which differ in the number and connectivity of methyl groups installed on the side chain of arginine (Figure a). ,,, Like other PTMs, Arg methylation creates a new binding epitope that triggers protein–protein interactions (PPIs). Tudor domains have been identified as the primary family of reader proteins responsible for binding histone Rme; these binding events dictate a range of cellular processes, including gene expression, through the recruitment of additional proteins to the nucleosome. ,− Structural studies have demonstrated that histone methylarginine is recognized by aromatic boxes within the Tudor domains, generally consisting of 4–5 aromatic residues and/or one Asn, Gln, Asp, or Glu residue. − Notably, these aromatic boxes which bind methylarginine are distinct from the more spherical aromatic cages which bind tetraalkylammoniums. , …”

“…14−19 Notably, these aromatic boxes which bind methylarginine are distinct from the more spherical aromatic cages which bind tetraalkylammoniums. 16,20 Despite the prevalence of Rme2 in histones and other proteins, much less is known about this PTM and its recognition relative to other PTMs, such as lysine methylation, in large part due to significantly weaker binding affinities by readers, often with K D > 100 μM. 10 Given the role of Arg methylation in mediating PPIs in epigenetic regulation, 15,19,21 we aimed to investigate the factors by which Arg methylation influences binding.…”

Binding methylarginines and methyllysines as free amino acids: a comparative study of multiple supramolecular host classes

“…Lots of research has been focused on binding methylated lysines, [21][22][23][24] while the selective binding of methylated arginine has received relatively less attention. 25,26 Most prior literature has focused on binding these methylated residues in the context of proteins and peptides. This study on free amino acids is motivated by a body of literature 15,18,[27][28][29] demonstrating that some of the free methylated amino acids are metabolites that play critical biological roles in pathways that are distinct from those involving whole proteins, protein tails, and peptides with post-translationally methylated residues.…”