The Cation−π Interaction at Protein–Protein Interaction Interfaces: Developing and Learning from Synthetic Mimics of Proteins That Bind Methylated Lysines

First discovered over 60 years ago, post-translational methylation was considered an irreversible modification until the initial discoveries of demethylase enzymes in 2004. Now researchers understand that this process serves as a dynamic and complex control mechanism that is misregulated in numerous diseases. Lysine methylation is most often found on histone proteins and can effect gene regulation, epigenetic inheritance, and cancer. Because of this connection to disease, many enzymes responsible for methylation are considered targets for new cancer therapies. Although our understanding of the biology of post-translational methylation has advanced at an astonishing rate within the last 5 years, chemical approaches for studying and disrupting these pathways are only now gaining momentum. In general, enzymes methylate lysine and arginine residues with very high specificity for both the location and methylation state. Each methylated target serves as the focused hot spot for an inducible protein-protein interaction (PPI). Conceptually, lysine or arginine methylation is a subtle modification that leads to no change in charge and small changes in size, but it significantly alters the hydration energies and hydrogen bonding potential of these side chains. Nature has evolved a special motif for recognizing the methylation states of lysine, called the "aromatic cage", a collection of aromatic protein residues, often accompanied by one or more neighboring anionic residues. The combination of favorable cation-π, electrostatic, and van der Waals interactions, as well as size matching, gives these proteins a high degree of specificity for the methylation state. This Account summarizes the development of various supramolecular host system scaffolds developed to recognize and bind to ammonium cations, such as trimethyllysine, on the basis of their methylation state. Early systems bound to their targets in pure, buffered water but failed to achieve biochemically relevant affinities and selectivities. Surprisingly, the use of the simple and very well-known p-sulfonatocalix[4]arene provides protein-like affinities and selectivities for trimethyllysine in water. New analogs, created by synthetic modification of the same scaffold, allow for further tuning of affinities and selectivities for trimethyllysine. Our studies of each family of hosts paint a consistent picture: cation-π interactions and electrostatics are important, and solvation effects are complex. Rigidity is especially important for host-guest systems that function in pure water. Despite their simplicity, synthetic systems that take these lessons into account can achieve affinities that rival or surpass those of their naturally evolved counterparts. The stage is now set for the next act: the use of such compounds as tunable and adaptable tools for modern chemical biology.

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