Thermodynamic penalty arising from burial of a ligand polar group within a hydrophobic pocket of a protein receptor.
Here, we examine the thermodynamic penalty arising from burial of a polar group in a hydrophobic pocket that forms part of the binding-site of the major urinary protein (MUP-I). X-ray crystal structures of the complexes of octanol, nonanol and 1,8 octan-diol indicate that these ligands bind with similar orientations in the binding pocket. Each complex is characterised by a bridging water molecule between the hydroxyl group of Tyr120 and the hydroxyl group of each ligand. The additional hydroxyl group of 1,8 octan-diol is thereby forced to reside in a hydrophobic pocket, and isothermal titration calorimetry experiments indicate that this is accompanied by a standard free energy penalty of +21 kJ/mol with respect to octanol and +18 kJ/mol with respect to nonanol. Consideration of the solvation thermodynamics of each ligand enables the "intrinsic" (solute-solute) interaction energy to be determined, which indicates a favourable enthalpic component and an entropic component that is small or zero. These data indicate that the thermodynamic penalty to binding derived from the unfavourable desolvation of 1,8 octan-diol is partially offset by a favourable intrinsic contribution. Quantum chemical calculations suggest that this latter contribution derives from favourable solute-solute dispersion interactions.
Barratt
Elizabeth
E
Astbury Centre for Structural Molecular Biology, School of Biochemistry and Molecular Biology, University of Leeds, LS2 9JT, UK.
Bronowska
Agnieszka
A
Vondrásek
Jirí
J
Cerný
Jirí
J
Bingham
Richard
R
Phillips
Simon
S
Homans
Steve W
SW
D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013816:Thermodynamics
D008024:Ligands; D011506:Proteins; C035737:major urinary proteins