Energetics of the protein-DNA-water interaction.

Francesca Spyrakis,Chiara Bertoli,Andrea Mozzarelli,Pietro Cozzini,Anna Marabotti,Glen E Kellogg

doi:10.1186/1472-6807-7-4

Abstract

BackgroundTo 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.ResultsAn 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.ConclusionThis 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.

Highlights

To understand the energetics of the interaction between protein and DNA we analyzed 39 crystallographically characterized complexes with the HINT (Hydropathic INTeractions) computational model
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 mostly cancel
From the analysis of the first protein-DNA crystal structure it was evident that several distinct contributions lead to formation of the complex [8,9,10], i.e., hydrogen bonds, electrostatic interactions, direct and indirect contacts between amino acids and phosphate, sugars and bases, water-mediated contacts, hydrophobic effects, ion release, mutual conformation rearrangement, bending and distortion

Summary

Introduction

To understand the energetics of the interaction between protein and DNA we analyzed 39 crystallographically characterized complexes with the HINT (Hydropathic INTeractions) computational model. Macromolecular recognition is based on the requirement of dual geometric and chemical complementarity, eventually leading to the formation of a thermodynamically stable and specific complex between interacting molecules. These aspects are key elements for understanding the (page number not for citation purposes). From the analysis of the first protein-DNA crystal structure it was evident that several distinct contributions lead to formation of the complex [8,9,10], i.e., hydrogen bonds, electrostatic interactions, direct and indirect contacts between amino acids and phosphate, sugars and bases, water-mediated contacts, hydrophobic effects, ion release, mutual conformation rearrangement, bending and distortion. Water molecules in free and protein-bound DNA complexes have been thoroughly investigated both experimentally and theoretically, and different roles have been proposed for interaction and recognition (see [14,15,16] and references therein)

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