title: Energetics of the protein-DNA-water interaction.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Parma, viale Usberti 23/A, 43100 Parma, Italy. fspyraki@nemo.unipr.it <fspyraki@nemo.unipr.it>
authors.forename: Francesca
authors.initials: F
authors.lastname: Spyrakis
authors.forename: Pietro
authors.initials: P
authors.lastname: Cozzini
authors.forename: Chiara
authors.initials: C
authors.lastname: Bertoli
authors.forename: Anna
authors.initials: A
authors.lastname: Marabotti
authors.forename: Glen E
authors.initials: GE
authors.lastname: Kellogg
authors.forename: Andrea
authors.initials: A
authors.lastname: Mozzarelli
mesh_terms: D019295:Computational Biology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D015394:Molecular Structure; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry*
chemical_list: D011506:Proteins; D014867:Water; D004247:DNA