What Drives Proteins into the Major or Minor Grooves of DNA?

Abstract

The energetic profiles of a significant number of protein-DNA systems at 20°C reveal that, despite comparable Gibbs free energies, association with the major groove is primarily an enthalpy driven process, whereas binding to the minor groove is characterized by an unfavorable enthalpy that is compensated by favorable entropic contributions. These distinct energetic signatures for major versus minor groove binding are irrespective of the magnitude of DNA bending and/or the extent of binding-induced protein refolding. The primary determinants of their different energetic profiles appear to be the distinct hydration properties of the major and minor grooves, namely that the water in the AT-rich minor groove is in a highly ordered state and its removal results in a substantial positive contribution to the binding entropy. Since the entropic forces driving protein binding into the minor groove are a consequence of displacing water ordered by the regular arrangement of polar contacts, they cannot be regarded as hydrophobic. KeywordsDNA binding; DNA grooves; hydration; thermodynamics; electrostatics Structural and energetic characterizations of protein-nucleic acid complexes are important for a better understanding of the molecular interactions that govern transcriptional regulation. Of particular importance are the energetic profiles of DNA binding domains (DBDs) interacting with their target recognition sites. DBDs are known to interact specifically with either the major or minor grooves of DNA, with binding-induced structural effects ranging from negligible perturbation of the B-DNA conformation to substantial distortions, such as bending and kinking. One can then ask if there are qualitative differences in the forces driving protein binding to the different grooves of DNA. Comparing the association constants of these two types of DBDs does not furnish a satisfactory answer, since both categories contain examples of stronger and weaker binding interactions. An answer to this question therefore requires a detailed analysis of the forces involved in the formation of the specific protein-DNA complexes. This assumes not only measurement of the association constant but also determination of the Gibbs energy and its enthalpic and entropic components over a broad range of conditions, particularly temperature and ionic strength. In this review, we analyze the thermodynamic characteristics of protein binding to DNA published over the last several years. This overall consideration has revealed qualitative differences in the energetic signatures of

Polycation-Mediated Gene Delivery: The Physicochemical Aspects Governing the Process

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