TY - JOUR
T1 - Thermodynamic Penalty Arising from Burial of a Ligand Polar Group Within a Hydrophobic Pocket of a Protein Receptor
AU - Barratt, Elizabeth
AU - Bronowska, Agnieszka
AU - Vondrášek, Jiří
AU - Černý, Jiří
AU - Bingham, Richard
AU - Phillips, Simon
AU - Homans, Steve W.
PY - 2006/10/6
Y1 - 2006/10/6
N2 - 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.
AB - 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.
KW - binding
KW - hydrophobicity
KW - ITC
KW - ligand-protein interactions
KW - Thermodynamics
UR - http://www.scopus.com/inward/record.url?scp=33748637583&partnerID=8YFLogxK
UR - https://www.sciencedirect.com/journal/journal-of-molecular-biology
U2 - 10.1016/j.jmb.2006.07.067
DO - 10.1016/j.jmb.2006.07.067
M3 - Article
C2 - 16935302
AN - SCOPUS:33748637583
VL - 362
SP - 994
EP - 1003
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 5
ER -