DNA mimicking proteins: discovery, design and evolution

Mimicry is a widely adopted strategy in biological conflicts. The focus of this proposal is the molecular mimicry of DNA by proteins. Such proteins harbour a surface and charge distribution similar to DNA. Currently, we know very little about DNA mimicking proteins. The few examples we know perturb key pathways, such as bacterial defence systems, transcription or chromatin. By implication, the engineering of these proteins toward specific targets could provide tailored inhibitors of DNA-binding proteins. This project will combine computational structural biology, large-scale phylogenomics, genetics, and experimental evolution to bring about a step change in our understanding of DNA mimics. We will use innovative protein surface homology modelling to discover new DNA mimicking proteins, and directed evolution to design novel ones. We will use phylogenomic analysis and genetics to investigate the impact of DNA mimicking proteins on bacterial genome function and evolution, particularly in relation to the acquisition of new genetic material by bacterial pathogens. This study will contribute to a broader understanding of the role of mimicry in biology and could have significant implications for the development of novel therapeutic agents that target DNA-binding proteins.