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 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.

Thermodynamic consequences of Tyr to Trp mutations in the cation–π-mediated binding of trimethyllysine by the HP1 chromodomain

“…5,6 Nonetheless, there is a dearth of direct experimental data in proteins demonstrating that Trp provides a greater driving force for cation-p interactions than Phe or Tyr. [7][8][9][10][11][12][13] The recognition of trimethyllysine (Kme3) on histone proteins by Kme3 reader proteins is a biologically and medicinally relevant group of PPIs mediated by cation-p interactions. These epigenetic PPIs, which mediate gene expression, have Electrostatic potentials were calculated in Spartan at the B3LYP/6-31G* level of theory (+100 to À100 kcal mol À1 ).…”

Amino acid modifications for conformationally constraining naturally occurring and engineered peptide backbones: Insights from the Protein Data Bank

“…Increasing the Cα bound ring size, increased the binding affinity of these oligopeptides for growth factor receptor‐bound protein 2 (Grb2)—ranging from 1.6 ±0.1 × 10 5 M −1 for 3‐carbon ring structure, to 69.6 ±12.0 × 10 5 M −1 . The oligopeptide with the largest (7‐carbon ring) modified amino acid in complex with Grb2 is illustrated in Figure (PDB ID 3ove, with the modified amino acid 03E) . Note that the torsion angles of the component 03E in this structure is similar to those seen for Aib ( φ = −61° and ψ = −36°), hence the impact of including these building blocks is introducing rigidity. Linkers and Staples: These components have a chiral Cα atom, with methyl groups as one substituent and varying sized linear aliphatics as the other (e.g., MK8, MH8, 5GM, and 0EH, Figure ).…”

“…Structure of SH2 domain of the Grb2 (grey) bound to a designed tri‐peptide inhibitor, containing an α,α‐cycloaliphatic amino acid (seven membered ring at the Cα position) and a C‐terminal O‐phosphotyrosine (PDB ID 3ove) . The Grb2 protein is represented as a ribbon and ball and stick structure.…”

Natural Products and Their Mimics as Targets of Opportunity for Discovery

“…211 Collectively, these and other studies of protein–ligand interactions involving both the Grb2 and Src SH2 domains as well as numerous other biological systems reveal the difficulties of interpreting how even incremental structural changes in small molecules affect binding enthalpies and entropies in their interactions with a target protein. 188 However, it is only through detailed studies of structure and energetics in protein–ligand interactions that any real understanding will emerge.…”