Protein mimicry of DNA and pathway regulation

The discoveries of DNA mimicry by proteins inspired by Ugi experiments led by Dale Mosbaugh and his colleagues have sparked dramatic insights for our understanding of DNA and protein interactions. Currently only a small number protein mimics of DNA are known or suspected, including Ugi, HI1450, Ocr, TAF1, MfpA, and Dinl. These proteins are structurally diverse, but together they share common themes we define here. These mimics tend to resemble distorted rather than normal B-DNA, possibly to prevent cross-reactions with other DNA metabolizing proteins that should not be inhibited. Side-chain carboxylates of glutamates and aspartates functionally replace phosphates and thereby generate an overall charge pattern resembling the DNA phosphate backbone. Most protein mimics of DNA have strikingly hydrophobic cores that likely stabilize the protein fold despite substantial charge localization and a relatively small internal volume enforced by the restrictions from DNA size. These common characteristics for protein mimicry of DNA should prove useful for future identifications of DNA mimics, which seem likely to be found in bacteriophages, conjugative plasmids, eukaryotic viruses, and transcription machinery. We also suggest approaches to the design of novel DNA mimics to inhibit specific pathways and could be important for basic science applications and for use as therapeutic agents. Moreover, mimicry in general is of critical importance in that it provides an elegant mechanism by which interfaces can be reused to force sequential rather than simultaneous complex formations such as seen in systems involving polar protein assemblies and DNA repair machinery.