The design of molecules that bind tightly and selectively to proteins is of high interest in the scientific community. Maximizing binding affinity (Ka) is important, but discerning the entropic and enthalpic contributions to protein-ligand binding is imperative in understanding how a ligand's structure affects the binding event. Association of hydrophobic ligands with the mouse major urinary protein (MUP-I) is characterized by enthalpy driven binding, a phenomenon described as a �non-classical hydrophobic effect,� with larger hydrophobic ligand surfaces showing an increase in Ka. Interest in 4-ethylphenol, a pheromone of MUP-I, has driven the current study of the synthesis and binding of para-phenol analogues in which the carbon chain is extended and branched. The protein-ligand complexes have been analyzed by X-ray crystallography, and isothermal titration calorimetry studies revealed that binding affinity and favorable enthalpic contributions not only increase with the chain length extended, but increase even more with the carbon chain branched.

Binding thermodynamics of para-substituted phenols to the mouse major urinary protein

245th National Meeting (2013)

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