Open AccessThermodynamic and Structural Effects of Macrocyclic Constraints in Protein−Ligand Interactions
Author(s) -
John E. DeLorbe,
John H. Clements,
Benjamin B. Whiddon,
Stephen F. Martin
Publication year - 2010
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/ml100142y
Subject(s) - isothermal titration calorimetry , chemistry , intramolecular force , hydrogen bond , enthalpy , ligand (biochemistry) , crystallography , protein ligand , energetics , titration , stereochemistry , molecule , thermodynamics , biochemistry , receptor , physics , organic chemistry
The thermodynamic and structural effects of macrocyclization as a tactic for stabilizing the biologically-active conformation of Grb2 SH2 binding peptides were investigated using isothermal titration calorimetry and x-ray crystallography. 23-Membered macrocycles containing the sequence pYVN were slightly more potent than their linear controls; however, preorganization did not necessarily eventuate in a more favorable binding entropy. Structures of complexes of macrocycle 7 and its acyclic control 8 are similar except for differences in relative orientations of corresponding atoms in the linking moieties of 7 and 8. There are no differences in the number of direct or water-mediated protein-ligand contacts that might account for the less favorable binding enthalpy of 7; however, an intramolecular hydrogen bond between the pY and pY+3 residues in 8 that is absent in 7 may be a factor. These studies highlight the difficulties associated with correlating energetics and structure in protein-ligand interactions.