Thermodynamic Penalty Arising from Burial of a Ligand Polar Group Within a Hydrophobic Pocket of a Protein Receptor

Elizabeth Barratt, Agnieszka Bronowska, Jiří Vondrášek, Jiří Černý, Richard Bingham, Simon Phillips, Steve W. Homans

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)994-1003
Number of pages10
JournalJournal of Molecular Biology
Volume362
Issue number5
DOIs
Publication statusPublished - 6 Oct 2006
Externally publishedYes

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