A bridge between the RNA and protein worlds? Accelerating delivery of chemical reactivity to RNA and DNA by a specific short peptide (AAKK)₄

Background: RNA can catalyze diverse chemical reactions, leading to the hypothesis that an RNA world existed early in evolution. Today, however, catalysis by naturally occurring RNAs is rare and most chemical transformations within cells require proteins. This has led to interest in the design of small peptides capable of catalyzing chemical transformations. Results: We demonstrate that a short lysine-rich peptide (AAKK)₄ can deliver a nucleophile to DNA or RNA and amplify the rate of chemical modification by up to 3400-fold. We also tested similar peptides that contain ornithine or arginine in place of lysine, peptides with altered stereochemistry or orientation, and peptides containing eight lysines but with different spacing. Surprisingly, these similar peptides function much less well, suggesting that specific combinations of amino acids, charge distribution, and stereochemistry are necessary for the rate enhancement by (AAKK)₄. Conclusions: By appending other reactive groups to (AAKK)₄ it should be possible to greatly expand the potential for small peptides to directly catalyze modification of DNA or RNA or to act as cofactors to promote ribozyme catalysis.