Structural and thermodynamic strategies for site-specific DNA binding proteins

Background: Site-specific protein-DNA complexes vary greatly in structural properties and in the thermodynamic strategy far achieving an appropriate b inding free energy. A better understanding of the structural and energetic engineering principles might lead to rational methods for modification or d esign of such proteins. Results: A novel analysis of ten site-specific protein-DNA complexes reveal s a striking correspondence between the degree of imposed DNA distortion an d the thermodynamic parameters of each system. For complexes with relativel y undistorted DNA, favorable enthalpy change drives unfavorable entropy cha nge, whereas for complexes with highly distorted DNA, unfavorable DeltaH de grees is driven by favorable DeltaS degrees. We show for the first time tha t protein-DNA associations have isothermal enthalpy-entropy compensation, d istinct from temperature-dependent compensation, so DeltaH degrees and Delt aS degrees do not vary independently. All complexes have favorable DeltaH d egrees from direct protein-DNA recognition interactions and favorable Delta S degrees from water release. Systems that strongly distort the DNA neverth eless have net unfavorable DeltaH degrees as the result of molecular strain , primarily associated with the base pair destacking. These systems have li ttle coupled protein folding and the strained interface suffers less immobi lization, so DeltaS degrees is net favorable. By contrast, systems with lit tle DNA distortion have net favorable DeltaH degrees, which must be counter balanced by net unfavorable DeltaS degrees, derived from loss of vibrationa l entropy (a result of isothermal enthalpy-entropy compensation) and from c oupling between DNA binding and protein folding. Conclusions: Isothermal enthalpy-entropy compensation implies that a struct urally optimal, unstrained fit is achieved only at the cost of entropically unfavorable immobilization, whereas an enthalpically weaker, strained inte rface entails smaller entropic penalties.