Increased protein backbone conformational entropy upon hydrophobic ligand binding

For complexes between proteins and very small hydrophobic ligands, hydropho bic effects alone map be insufficient to outweigh the unfavorable entropic terms resulting from bimolecular association. NMR relaxation experiments in dicate that the backbone flexibility of mouse major urinary protein increas es upon binding the hydrophobic mouse pheromone 2-sec-butyl-4,5-dihydrothia zole. The associated increase in backbone conformational entropy of the pro tein appears to make a substantial contribution toward stabilization of the protein-pheromone complex. This term is likely comparable in magnitude to other important free energy contributions to binding and map represent a ge neral mechanism to promote binding of very small ligands to macromolecules.