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  • Title: Empirical free energy calculations of phage 434 repressor- and cro-DNA complexes support the 'indirect readout' hypothesis of specificity.
    Author: Brown LM, Bruccoleri RE, Novotny J.
    Journal: Pac Symp Biocomput; 1998; ():339-48. PubMed ID: 9697194.
    Abstract:
    Empirical free energy calculations were done for two X-ray DNA-protein complexes. Complex formation energies were estimated for the phage 434 repressor and the 434 cro protein, both in complex with wild-type versions of their respective nucleic acid binding sites. The resulting quantities were subdivided according to the relative contributions of hydrophobicity, electrostatics and entropy (including both conformational changes and those pertinent to physical association of complex components). The non-linearized finite difference Poisson-Boltzmann equation was solved over a range of salt concentrations to determine magnitudes of coulombic and desolvation effects. Though approximate at best, results confirmed (1) the importance of centrally located charged protein residues that do not make direct contact with the DNA, (2) explicit protein backbone interactions with DNA, and (3) the varied parts of the two proteins used to harness the energy of binding. Although a large difference exists between calculated and experimentally measured free energy values, these can be reconciled by assuming that approximately 1.5 e.u. (about 0.4-0.5 kcal at room temperature) of DNA vibrational and/or conformational entropy is lost for every basepair torsion in contact with the protein. Such a conclusion supports an "indirect readout" ("compound recognition") hypothesis of DNA binding specificity, wherein sequence-dependent differences in protein-DNA interaction are due to the topological peculiarities of the interactions rather than intrinsic chemical differences alone.
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