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Energetics of the protein-DNA-water interaction

Francesca Spyrakis1, Pietro Cozzini25*, Chiara Bertoli1, Anna Marabotti34, Glen E Kellogg5* and Andrea Mozzarelli1*

Author Affiliations

1 Department of Biochemistry and Molecular Biology, University of Parma, viale Usberti 23/A, 43100 Parma, Italy

2 Laboratory of Molecular Modeling, Department of General and Inorganic Chemistry, University of Parma, Viale Usberti 17/A, 43100 Parma, Italy

3 Laboratory for Bioinformatics and Computational Biology, Institute of Food Science, National Research Council, Via Roma 52 A/C, 83100 Avellino, Italy

4 Interdepartmental Research Center for Computational and Biotechnological Sciences (CRISCEB), Second University of Naples, Via S. Maria di Costantinopoli 16, 80138 Naples, Italy

5 Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, Virginia, 23298-0540, USA

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BMC Structural Biology 2007, 7:4  doi:10.1186/1472-6807-7-4

Published: 10 January 2007



To understand the energetics of the interaction between protein and DNA we analyzed 39 crystallographically characterized complexes with the HINT (Hydropathic INTeractions) computational model. HINT is an empirical free energy force field based on solvent partitioning of small molecules between water and 1-octanol. Our previous studies on protein-ligand complexes demonstrated that free energy predictions were significantly improved by taking into account the energetic contribution of water molecules that form at least one hydrogen bond with each interacting species.


An initial correlation between the calculated HINT scores and the experimentally determined binding free energies in the protein-DNA system exhibited a relatively poor r2 of 0.21 and standard error of ± 1.71 kcal mol-1. However, the inclusion of 261 waters that bridge protein and DNA improved the HINT score-free energy correlation to an r2 of 0.56 and standard error of ± 1.28 kcal mol-1. Analysis of the water role and energy contributions indicate that 46% of the bridging waters act as linkers between amino acids and nucleotide bases at the protein-DNA interface, while the remaining 54% are largely involved in screening unfavorable electrostatic contacts.


This study quantifies the key energetic role of bridging waters in protein-DNA associations. In addition, the relevant role of hydrophobic interactions and entropy in driving protein-DNA association is indicated by analyses of interaction character showing that, together, the favorable polar and unfavorable polar/hydrophobic-polar interactions (i.e., desolvation) mostly cancel.