CONSISTENCY IN STRUCTURAL ENERGETICS OF PROTEIN-FOLDING AND PEPTIDE RECOGNITION

We report a new free energy decomposition that includes structure-deri ved atomic contact energies for the desolvation component, and show th at it applies equally well to the analysis of single-domain protein fo lding and to the binding of flexible peptides to proteins. Specificall y, we selected the 17 single-domain proteins for which the three-dimen sional structures and thermodynamic unfolding free energies are availa ble. By calculating all terms except the backbone conformational entro py change and comparing the result to the experimentally measured free energy, we estimated that the mean entropy gain by the backbone chain upon unfolding (Delta S-bb) is 5.3 cal/K per mole of residue, and tha t the average backbone entropy for glycine is 6.7 cal/K. Both numbers are in close agreement with recent estimates made by entirely differen t methods, suggesting a promising degree of consistency between data o btained from disparate sources. Tn addition, a quantitative analysis o f the folding free energy indicates that the unfavorable backbone entr opy for each of the proteins is balanced predominantly by favorable ba ckbone interactions. Finally, because the binding of flexible peptides to receptors is physically similar to folding, the free energy functi on should, in principle, be equally applicable to flexible docking. By combining atomic contact energies, electrostatics, and sequence-depen dent backbone entropy, we calculated a priori the free energy changes associated with the binding of four different peptides to HLA-A2.1 MHC molecule and found agreement with experiment to within 10% without pa rameter adjustment.