Post-translational modifications of proteins are a key component of cell signaling. In particular, post-translational modifications of histone tails are known to modulate transcription of DNA. These modifications function via a number of different non-covalent interactions with both DNA and various nuclear proteins. Some relevant modifications include methylation or acylation of lysine and the methylation of arginine and are thought to trigger binding with aromatic rings (Trp, DNA bases) through cation-π and amide-π interactions. In order to characterize these biologically relevant interactions, they have been studied within the context of β-hairpin peptide model systems, which enable the description and quantification of specific sidechain-sidechain interactions. In our system, the interaction between Trp and trimethylated Lys is shown to be worth 1.0 kcal/mol, a stabilization of about 0.7 kcal/mol over the nonmethylated Lys-Trp interaction. The methylated interaction occurs with an enhanced entropic driving force over the unmethylated interaction. Methylation of Arg is also shown to enhance its interaction with Trp, by about 0.5 kcal/mol. Additionally, the acyl Lys-Trp interaction is found to be equivalent in magnitude to the nonmethylated Lys-Trp interaction (0.3 kcal/mol). Acylation of lysine in our model system is shown to induce a switch from a cation-π to an amide-π interaction. Investigations into neutral analogues of trimethylated Lys reveals the critical nature of the cation-π interaction to the interaction of histone tails with chromodomain proteins. This is confirmed both in our β-hairpin model system and with binding studies with the HP1 chromodomain.

Additional investigations in this thesis include mutational studies of a β-hairpin receptor for ATP and the study of a cation-π interaction within a small molecule model system. Through experimental and computational studies, the β-hairpin receptor for ATP is shown to form a well-defined binding pocket with a number of important electrostatic contacts. The cation-π interaction in the small molecule model system is found to prevail in both aqueous and organic solvent, despite the possible presence of competing non covalent interactions. X-ray and computational evidence suggests the possible presence of an oxy-arene interaction in organic solvent, but the interpretation of conformational differences from NMR data is ambiguous.