Work

Influence of the Electrostatic Tuning of Alkyl and Benzyl Groups on Cation-π Interactions in Histone Reader Proteins and β-Hairpin Peptides

Year: 2026

Type: article

Abstract: Reader proteins that bind histone trimethyllysine (Kme3) have become active therapeutic targets in recent years. Binding of Kme3 in the conserved aromatic cages of these readers via cation-π interactions is a key contributor to these protein-protein interactions. We explored whether the replacement of one methyl group of Kme3 with an electron-withdrawing group (EWG) could improve binding by increasing the electrostatic component of the cation-π interaction. We examined these Kme3 analogs in binding studies with histone reader proteins, nuclear magnetic resonance (NMR) studies in a β-hairpin peptide model system, and computational studies to gain mechanistic insight into their binding. Kme3 analogs with both alkyl and benzyl substitution with EWGs were examined. We found that EWGs on the ligand differentially affected binding to a series of Kme3 readers but did not improve binding. This is likely due to sterics of the different analogs that preclude optimal cation-π interactions. The unique selectivity patterns of these ligands nonetheless offer promise toward selective inhibitor development within this protein class. NMR studies of the alkyl-substituted analogs in the β-hairpin model system show that EWGs strengthen the cation-π interaction enthalpically but with an entropic penalty. NMR studies demonstrate that the benzyl group makes direct contacts with Trp in the β-hairpin model, providing aromatic interactions in addition to cation-π interactions. Computational energy decomposition analysis confirms the more favorable electrostatic interactions compared to Kme3, but other factors counter the enhanced electrostatic component. This mechanistic investigation demonstrates how EWG-containing Kme3 analogs contribute to cation-π interactions and provide unique selectivity patterns relative to Kme3.

Source: Biochemistry

DOI: 10.1021/acs.biochem.5c00531

Authors: Meghan N. Ricciardi, Christopher R. Travis, Joseph W. Treacy, John M. Boniberger, K. N. Houk, Marcey L. Waters

Institutions: University of North Carolina at Chapel Hill, University of California, Los Angeles

Language: English

Topic: Crystallography and molecular interactions

Subfield: Physical and Theoretical Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: green

Funders: National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Science Foundation Graduate Research Fellowship Program

Awards: G2717461293, G2738462660, G4448310094