Protein-DNA recognition is crucial for a variety of biological processes such as transcription and regulation of genome accessibility. Proteins may recognize DNA sequence through specific hydrogen bonds to the bases. However, proteins often recognize DNA shape by interacting with DNA which is deformed. This interplay between the recognition of DNA sequence and shape necessitates examination of both sequence and structure as they relate to protein-DNA recognition.

Analysis of all X-ray crystallographic structures of proteins which contact the DNA revealed a widespread readout mechanism involving shape readout of the DNA minor groove. The width of the DNA backbone along the minor groove is tightly linked to the electrostatic potential in and around the minor groove, even more than to the base identity. Proteins are able to use basic amino acids, most commonly arginine, to recognize narrow minor grooves, which have increased negative electrostatic potential. Often, AT-rich sequences, which are intrinsically narrow, are recognized in this manner. Furthermore, arginines are used to stabilize the highly deformed DNA of the nucleosome by inserting into narrow minor grooves of the DNA as it wraps around the histone octamer.

In our analysis of structures of nucleosome core particles, two drastically different DNA sequences gave rise to similar minor groove widths, despite variance of the helical parameters. This indicates that the shape of DNA is being induced to conform to the histone-DNA interface. However, histone octamers do not bind in a completely non-specific manner; there are regions of the genome which have no nucleosome occupancy as well as regions which have strongly positioned nucleosomes. Our research shows the in vivo positioning of nucleosomes along the genome is related to the frequency and length of A-tracts.

Our results demonstrate the importance of using both sequence and structural information in studying protein-DNA recognition. By analyzing all available protein-DNA structures, as well as the sequences bound by proteins, we have contributed to the community's understanding of protein-DNA recognition.