2DM5

Thermodynamic penalty arising from burial of a ligand polar group within a hydrophobic pocket of a protein receptor

(2006) J Mol Biol 362: 994-1003

• PubMed: 16935302 Search on PubMed
• DOI: https://doi.org/10.1016/j.jmb.2006.07.067
• Primary Citation of Related Structures:  
  2DM5


• PubMed Abstract: 
  

  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.

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Organizational Affiliation: 

Astbury Centre for Structural Molecular Biology, School of Biochemistry and Molecular Biology, University of Leeds, LS2 9JT, UK.