Insights into protein-DNA interactions from hydrogen bond energy-based comparative protein-ligand analyses.

Hydrogen bonds play important roles in protein folding and protein-ligand interactions, particularly in specific protein-DNA recognition. However, the distributions of hydrogen bonds, especially hydrogen bond energy (HBE) in different types of protein-ligand complexes, is unknown. Here we performed a comparative analysis of hydrogen bonds among three non-redundant datasets of protein-protein, protein-peptide, and protein-DNA complexes. Besides comparing the number of hydrogen bonds in terms of types and locations, we investigated the distributions of HBE. Our results indicate that while there is no significant difference of hydrogen bonds within protein chains among the three types of complexes, interfacial hydrogen bonds are significantly more prevalent in protein-DNA complexes. More importantly, the interfacial hydrogen bonds in protein-DNA complexes displayed a unique energy distribution of strong and weak hydrogen bonds whereas majority of the interfacial hydrogen bonds in protein-protein and protein-peptide complexes are of predominantly high strength with low energy. Moreover, there is a significant difference in the energy distributions of minor groove hydrogen bonds between protein-DNA complexes with different binding specificity. Highly specific protein-DNA complexes contain more strong hydrogen bonds in the minor groove than multi-specific complexes, suggesting important role of minor groove in specific protein-DNA recognition. These results can help better understand protein-DNA interactions and have important implications in improving quality assessments of protein-DNA complex models.

A comparative study of protein-ssDNA interactions.

Single-stranded DNA-binding proteins (SSBs) play crucial roles in DNA replication, recombination and repair, and serve as key players in the maintenance of genomic stability. While a number of SSBs bind single-stranded DNA (ssDNA) non-specifically, the others recognize and bind specific ssDNA sequences. The mechanisms underlying this binding discrepancy, however, are largely unknown. Here, we present a comparative study of protein-ssDNA interactions by annotating specific and non-specific SSBs and comparing structural features such as DNA-binding propensities and secondary structure types of residues in SSB-ssDNA interactions, protein-ssDNA hydrogen bonding and π-π interactions between specific and non-specific SSBs. Our results suggest that protein side chain-DNA base hydrogen bonds are the major contributors to protein-ssDNA binding specificity, while π-π interactions may mainly contribute to binding affinity. We also found the enrichment of aspartate in the specific SSBs, a key feature in specific protein-double-stranded DNA (dsDNA) interactions as reported in our previous study. In addition, no significant differences between specific and non-specific groups with respect of conformational changes upon ssDNA binding were found, suggesting that the flexibility of SSBs plays a lesser role than that of dsDNA-binding proteins in conferring binding specificity.