Free-Energy Calculations of Protein−Ligand Cation−π and Amino−π Interactions: From Vacuum to Proteinlike Environments

• Published in: Journal of the American Chemical Society Vol. 125; no. 46; pp. 13988 - 13994
• Main Authors: Biot, Christophe, Buisine, Eric, Rooman, Marianne
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 19.11.2003
• Subjects: Amino Acids - chemistry; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cations - chemistry; Fundamental and applied biological sciences. Psychology; General aspects, investigation methods; Ligands; Proteins; Proteins - chemistry; Quantum Theory; Solvents - chemistry; Thermodynamics; Vacuum; Stability; Quantum chemistry; Ligand; Ab initio method; Carbon tetrachloride; Vibrational energy; Theoretical study; Molecular interaction; Cofactor; X ray diffraction; Tetrahydrofurane; Free energy; Protein; Amine; Side chain; Solvation; Cations; Minimum energy; Inclusion compound; Solvent; Interaction energy; Acetone
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja035223e

To probe the role of cation−π and amino−π interactions in the context of protein−ligand interactions, the stability of 55 X-ray cation/amino−π motifs involving the Ade moieties of cofactor molecules and Arg, Lys, Asn, or Gln side chains of their host protein was evaluated using quantum chemistry calculations. The conjunction of vacuum interaction energies, vibrational entropy, and solvation contributions led to identify Arg−Ade as the most favorable cation/amino−π complex in the solvents considered, followed by Asn/Gln−Ade and Lys−Ade:  their minimum interaction free energies are approximately equal to −7, −4, and −2 kcal/mol, respectively, in the solvents of dielectric constant similar to that estimated for proteins (i.e., acetone, THF, and CCl4). Remarkably, these free-energy values of cation/amino−π interactions correlate well with their frequency of occurrences in protein−ligand structures, which corroborates our approach in the absence of experimental data.