Dueling post-translational modifications trigger folding and unfolding of a beta-hairpin peptide.

Protein post-translational modifications (PTMs) are used in nature as a means of turning on or off a myriad of biological events. Methylation of lysine and phosphorylation of serine are important PTMs in the histone code found to modulate chromatin packing, which in turn affects gene expression. The design of peptides that fold into secondary structures can help to further our understanding of complex protein interactions. Here we report the design of the Trpswitch peptide sequence that folds into a moderately stable beta-hairpin structure in aqueous solution and show that the stability of the structure can be tuned by incorporation of dimethyllysine or phosphoserine. Dimethylated Trpswitch results in an increase in beta-hairpin stability, while phosphorylated Trpswitch is unstructured at neutral pH. When both modifications are incorporated into Trpswitch, a less stable beta-hairpin structure is observed. This system provides a model to demonstrate how multiple PTMs may work in concert or against each other to influence structure.