Free energy analysis of protein-DNA binding: The EcoRI endonuclease-DNA complex (Q1305988)

A detailed theoretical analysis of the thermodynamics and functional energetics of protein-DNA binding in the EcoRI endonuclease-DNA complex has been described. The standard free energy of complexation is considered in terms of a thermodynamic cycle of seven distinct steps decomposed into a total of 24 well-defined components. The model we employ involves explicit all-atom accounts of the energetics of structural adaptation of the protein and DNA on complex formation; the van der Waals and electrostatic interactions between the protein and the DNA; and the electrostatic polarization and screening effects, van der Waals components, and cavitation effects of solvation. The ion atmosphere of the DNA is described in terms of a counterion condensation model, which permits estimates of the ion release upon complexation and a Debye-Huckel treatment of added salt effects. Estimates of entropy loss due to decreased translational and rotational degrees of freedom in the complex relative to the unbound species based on classical statistical mechanics are included, as well as corresponding changes in the vibrational and configurational entropy. The magnitudes and signs of the various components are estimated from the AMBER parm94 force field, generalized Born theory, solvent accessibility measures, and empirical estimates of quantities related to ion release. The calculated standard free energy of formation, --11.5 kcal/mol, agrees with experiment to within 5 kcal/mol. Analysis of the results shows that the calculated binding free energy of the EcoRI endonuclease-DNA complex is the resultant of a balance of competing contributions associated with chemical forces as conventionally defined, with 10 of 24 terms favoring complexation.