Energetics of the protein-DNA-water interaction

Authors

Francesca Spyrakis, University of Parma
Pietro Cozzini, Virginia Commonwealth UniversityFollow
Chiara Bertoli, University of Parma
Anna Marabotti, Second University of Naples
Glen E. Kellogg, Virginia Commonwealth UniversityFollow
Andrea Mozzarelli, University of Parma

Document Type

Article

Original Publication Date

2007

Journal/Book/Conference Title

BMC Structural Biology

DOI of Original Publication

10.1186/1472-6807-7-4

Comments

Originally published at http://dx.doi.org/10.1186/1472-6807-7-4

Date of Submission

August 2014

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.

Conclusion 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.

Rights

© 2007 Spyrakis et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Is Part Of

VCU Medicinal Chemistry Publications