Thermodynamic parameters were determined for complex formation between the Grb2
SH2 domain and Ac-pTyr-Xaa-Asn derived tripeptides in which the Xaa residue is
an α,α-cycloaliphatic amino acid that varies in ring size from three- to
seven-membered. Although the six- and seven-membered ring analogs are
approximately equipotent, binding affinities of those having three- to
six-membered rings increase incrementally with ring size because increasingly
more favorable binding enthalpies dominate increasingly less favorable binding
entropies, a finding consistent with an enthalpy-driven hydrophobic effect.
Crystallographic analysis reveals that the only significant differences in
structures of the complexes are in the number of van der Waals contacts between
the domain and the methylene groups in the Xaa residues. There is a positive
correlation between buried nonpolar surface area and binding free energy and
enthalpy, but not with ΔC(p). Displacing a water molecule from a protein-ligand
interface is not necessarily reflected in a favorable change in binding entropy.
These findings highlight some of the fallibilities associated with commonly held
views of relationships of structure and energetics in protein-ligand
interactions and have significant implications for ligand design.
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