Protein-DNA interactions: Structural, thermodynamic and clustering patterns of conserved residues in DNA-binding proteins

Shandar Ahmad, Ozlem Keskin, Akinori Sarai*, Ruth Nussinov

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

80 Scopus citations


Amino acid residues, which play important roles in protein function, are often conserved. Here, we analyze thermodynamic and structural data of protein-DNA interactions to explore a relationship between free energy, sequence conservation and structural cooperativity. We observe that the most stabilizing residues or putative hotspots are those which occur as clusters of conserved residues. The higher packing density of the clusters and available experimental thermodynamic data of mutations suggest cooperativity between conserved residues in the clusters. Conserved singlets contribute to the stability of protein-DNA complexes to a lesser extent. We also analyze structural features of conserved residues and their clusters and examine their role in identifying DNA-binding sites. We show that about half of the observed conserved residue clusters are in the interface with the DNA, which could be identified from their amino acid composition; whereas the remaining clusters are at the protein-protein or protein-ligand interface, or embedded in the structural scaffolds. In protein-protein interfaces, conserved residues are highly correlated with experimental residue hotspots, contributing dominantly and often cooperatively to the stability of protein-protein complexes. Overall, the conservation patterns of the stabilizing residues in DNA-binding proteins also highlight the significance of clustering as compared to single residue conservation.

Original languageEnglish
Pages (from-to)5922-5932
Number of pages11
JournalNucleic Acids Research
Issue number18
StatePublished - 2008


FundersFunder number
National Institutes of HealthNO1-CO-12400
National Cancer Institute16014219, 16041235, ZIABC010441
Ministry of Education, Culture, Sports, Science and Technology


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