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Lookup NU author(s): Dr Agnieszka Bronowska, Professor Steve Homans
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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.
Author(s): Barratt E, Bronowska A, Vondrásek J, Cerny J, Bingham R, Phillips S, Homans SW
Publication type: Article
Publication status: Published
Journal: Journal of Molecular Biology
Year: 2006
Volume: 362
Issue: 5
Pages: 994-1003
ISSN (print): 0022-2836
Publisher: Academic Press
URL: http://dx.doi.org/10.1016/j.jmb.2006.07.067
DOI: 10.1016/j.jmb.2006.07.067
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