title: Protein-ligand interactions: probing the energetics of a putative cation-π interaction.
abstract: In order to probe the energetics associated with a putative cation-π interaction, thermodynamic parameters are determined for complex formation between the Grb2 SH2 domain and tripeptide derivatives of RCO-pTyr-Ac6c-Asn wherein the R group is varied to include different alkyl, cycloalkyl, and aryl groups. Although an indole ring is reputed to have the strongest interaction with a guanidinium ion, binding free energies, ΔG°, for derivatives of RCO-pTyr-Ac6c-Asn bearing cyclohexyl and phenyl groups were slightly more favorable than their indolyl analog. Crystallographic analysis of two complexes reveals that test ligands bind in similar poses with the notable exception of the relative orientation and proximity of the phenyl and indolyl rings relative to an arginine residue of the domain. These spatial orientations are consistent with those observed in other cation-π interactions, but there is no net energetic benefit to such an interaction in this biological system. Accordingly, although cation-π interactions are well documented as important noncovalent forces in molecular recognition, the energetics of such interactions may be mitigated by other nonbonded interactions and solvation effects in protein-ligand associations.
authors.affiliation: The Department of Chemistry, The Institute of Cellular and Molecular Biology, and the Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, TX 78712, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Myslinski
authors.affiliation: The Department of Chemistry, The Institute of Cellular and Molecular Biology, and the Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, TX 78712, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Clements
authors.affiliation: The Department of Chemistry, The Institute of Cellular and Molecular Biology, and the Texas Institute of Drug and Diagnostic Development, The University of Texas, Austin, TX 78712, USA. Electronic address: sfmartin@mail.utexas.edu.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin
mesh_terms: D051380:GRB2 Adaptor Protein / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D051380:GRB2 Adaptor Protein; D008024:Ligands; D009842:Oligopeptides
keywords: Binding thermodynamics; Molecular recognition; Protein–ligand interactions; Structure; X-ray crystallography