The four canonical bases that make up the basis of life are subject to various chemical modifications in living systems. Recent years have witnessed different modified genomic bases and the enzymes responsible for the processing. Understanding their role in human diseases is relevant, particularly in cancers and neurological disorders. Apart from cytosine methylation, including diverse mechanistic features, the roles of most epigenetic modifications remain poorly understood. This lack of understanding is derived from the difficulties in specifically identifying non-canonical bases in the DNA site. Tailored DNA reader proteins recognizing specific epigenetic marks may enable future genome interrogation with a resolution of single bases [1]. Understanding the structural and motional requirements of natural and artificial readers in interaction with dedicated DNA targets will be critical to generating diverse molecular probes to unravel chromatin biology and effectively understanding (aberrant) target recognition in a range of diseases. In this talk, I will discuss combined efforts utilizing mutations, NMR relaxation and structural studies, and MD simulations to show that the selectivity of the first designer DNA reader for an oxidized CpG duplex mark hinges on the precisely tempered conformational plasticity of the scaffold adopted during the directed evolution of a natural progenitor [2]. Our observations reveal the critical aspect of defined motional features in this novel reader for affinity and specificity in the DNA/protein interaction, providing unexpected prospects for further design progress in this unexplored area of DNA recognition.