Large-Scale Quantitative Assessment of Binding Preferences in Protein-Nucleic Acid Complexes

The growing number of high-quality experimental (X-ray, NMR) structures of protein–DNA complexes has sufficient enough information to assess whether universal rules governing the DNA sequence recognition process apply. While previous studies have investigated the relative abundance of various modes of amino acid–base contacts (van der Waals contacts, hydrogen bonds), relatively little is known about the energetics of these noncovalent interactions. In the present study, we have performed the first large-scale quantitative assessment of binding preferences in protein–DNA complexes by calculating the interaction energies in all 80 possible amino acid–DNA base combinations. We found that several mutual amino acid–base orientations featuring bidentate hydrogen bonds capable of unambiguous one-to-one recognition correspond to unique minima in the potential energy space of the amino acid–base pairs. A clustering algorithm revealed that these contacts form a spatially well-defined group offering relatively little conformational freedom. Various molecular mechanics force field and DFT-D ab initio calculations were performed, yielding similar results.