The Presence of Arginine Regulates the Selectivity and Binding Affinity of Lysine Receptors

Abstract

Post-translational modifications play an essential role in biological processes, such as gene expression and disease development. The methylation of lysine (Lys) on a histone protein, for example, can cause a gene to be repressed or activated. Dynamic combinatorial chemistry has been used to identify A2N as a synthetic receptor for trimethyllysine (Kme3). Recent studies have shown that A2N binds to Kme3 tighter than to non-methylated lysine (Kme0). When a neighboring arginine (Arg) was mutated to glycine, the binding of A2N to Kme0 and Kme3 weakened and A2N became more selective for Kme3. In sequences containing three Arg, A2N proved to bind to Kme0 and Kme3 significantly tighter as compared to the previous sequences. However, in this case A2N was considerably less selective for Kme3. We hypothesized that the presence of Arg affects the binding affinity and selectivity of Lys and by shifting the position of Arg further from Lys the binding would greatly weaken. We noticed that when Arg was shifted further from Kme0 and Kme3 the binding of A2N weakened, only partially in the tri-methylated state. As the distance between Arg and Lys increased A2N became more selective for Kme3. These findings suggest that Arg mediates the specificity of the binding affinity between Lys and A2N independent of location within the sequence with an improved selectivity for Kme3 as distance between Lys and Arg increased. The attraction between Arg and Lys will need to be further examined to understand the mechanism influencing the selectivity and binding properties of A2N to Lys. Increasing awareness of this relationship may help to modify synthetic receptors and better understand post-translational modifications.