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Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization

Thermodynamic and structural effects of conformational constraints in protein-ligand interactions. Entropic paradoxy associated with ligand preorganization

Journal of the American Chemical Society 131(46): 16758-16770

Succinate- and cyclopropane-derived phosphotyrosine (pY) replacements were incorporated into a series of Grb2 SH2 binding ligands wherein the pY+1 residue was varied to determine explicitly how variations in ligand preorganization affect binding energetics and structure. The complexes of these ligands with the Grb2 SH2 domain were examined in a series of thermodynamic and structural investigations using isothermal titration calorimetry and X-ray crystallography. The binding enthalpies for all ligands were favorable, and although binding entropies for all ligands having a hydrophobic residue at the pY+1 site were favorable, binding entropies for those having a hydrophilic residue at this site were unfavorable. Preorganized ligands generally bound with more favorable Gibbs energies than their flexible controls, but this increased affinity was the consequence of relatively more favorable binding enthalpies. Unexpectedly, binding entropies of the constrained ligands were uniformly disfavored relative to their flexible controls, demonstrating that the widely held belief that ligand preorganization should result in an entropic advantage is not necessarily true. Crystallographic studies of complexes of several flexible and constrained ligands having the same amino acid at the pY+1 position revealed extensive similarities, but there were some notable differences. There are a greater number of direct polar contacts in complexes of the constrained ligands that correlate qualitatively with their more favorable binding enthalpies and Gibbs energies. There are more single water-mediated contacts between the domain and the flexible ligand of each pair; although fixing water molecules at a protein-ligand interface is commonly viewed as entropically unfavorable, entropies for forming these complexes are favored relative to those of their constrained counterparts. Crystallographic b-factors in the complexes of constrained ligands are greater than those of their flexible counterparts, an observation that seems inconsistent with our finding that entropies for forming complexes of flexible ligands are relatively more favorable. This systematic study highlights the profound challenges and complexities associated with predicting how structural changes in a ligand will affect enthalpies, entropies, and structure in protein-ligand interactions.

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Accession: 056555365

Download citation: RISBibTeXText

PMID: 19886660

DOI: 10.1021/ja904698q

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