Enthalpy of hydrogen bond formation in a protein-ligand binding reaction.

AUTOR(ES)

Connelly, P R

RESUMO

Parallel measurements of the thermodynamics (free-energy, enthalpy, entropy and heat-capacity changes) of ligand binding to FK506 binding protein (FKBP-12) in H2O and D2O have been performed in an effort to probe the energetic contributions of single protein-ligand hydrogen bonds formed in the binding reactions. Changing tyrosine-82 to phenylalanine in FKBP-12 abolishes protein-ligand hydrogen bond interactions in the FKBP-12 complexes with tacrolimus or rapamycin and leads to a large apparent enthalpic stabilization of binding in both H2O and D2O. High-resolution crystallographic analysis reveals that two water molecules bound to the tyrosine-82 hydroxyl group in unliganded FKBP-12 are displaced upon formation of the protein-ligand complexes. A thermodynamic analysis is presented that suggests that the removal of polar atoms from water contributes a highly unfavorable enthalpy change to the formation of C=O...HO hydrogen bonds as they occur in the processes of protein folding and ligand binding. Despite the less favorable enthalpy change, the entropic advantage of displacing two water molecules upon binding leads to a slightly more favorable free-energy change of binding in the reactions with wild-type FKBP-12.

Documentos Relacionados

• Femtosecond studies of protein–ligand hydrophobic binding and dynamics: Human serum albumin
• The relationship between ligand-binding thermodynamics and protein-ligand interaction forces measured by atomic force microscopy.
• Comparing protein–ligand interactions in solution and single crystals by Raman spectroscopy
• Characterization of the sources of protein-ligand affinity: 1-sulfonato-8-(1')anilinonaphthalene binding to intestinal fatty acid binding protein.
• Thermodynamics of water mediating protein-ligand interactions in cytochrome P450cam: a molecular dynamics study.