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

22 September 2021, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Methylated free amino acids are an important class of targets for host-guest chemistry that have recognition properties distinct from those of methylated peptides and proteins. We present comparative binding studies for three different host classes that are each studied with multiple methylated arginines and lysines to determine fundamental structure-function relationships. The hosts studied are all anionic and include three calixarenes, two acyclic cucurbiturils, and two cleft-like hosts. We determined the binding association constants for a panel of methylated amino acids using indicator displacement assays. The calixarene hosts show weak binding that favours the higher methylation states, with the strongest binding observed for trimethyllysine. The acyclic cucurbiturils display stronger binding to the methylated amino acids, and some unique patterns of selectivity. The cleft-like hosts follow two different trends, one shallow host following similar trends to the calixarenes, and the other more closed host binding certain less-methylated amino acids stronger than their per-methylated counterparts. Molecular modeling sheds some light on the different preferences of different hosts. The results identify hosts with selectivities that will be useful for certain biomedical applications. The overall selectivity patterns are explained by a common framework that considers the topology, depth of binding pockets, and functional group participation across all host classes.


host-guest chemistry
methylated amino acids
indicator displacement assays


Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.