Book of Abstracts: Albany 2003
June 17-21 2003
Cation-π Interactions at Protein-ligand Interfaces: In silico Free Energy Estimation and Environment Dependency
A set of 188 high resolution X-ray structures of proteins bound to cofactor molecules were systematically searched for cation-π interactions between adenine, the most frequent nucleotide ligand building block, and a positively charged (Arg and Lys) or partially charged side chain group (Asn and Gln). Ab initio quantum chemistry calculations were performed at MP2 level on all the complexes, and were corrected for basis set superposition errors using the classical counterpoise method. The cation-π energy contribution in vacuum was shown to be essentially of electrostatic nature for Lys, due to electronic correlation for Asn and Gln, and half-electrostatic half-correlation for Arg, on the average. We also investigated the contributions of the solvation, vibrational entropy and zero point energy (ZPE) to the interaction free energy of protein-ligand cation-π pairs. Protein environments surrounding the adenine moiety were mimicked by varying the solvent. Five different solvents with a dielectric constant ranging from 2 (CCl4) to 78 (H2O) and two different continuum solvent models (IEF-PCM and SM5.4/A) were tested. The results can be briefly summarized as follows: (i) the interaction ZPE's are negligible for all the considered pairs, (ii) the vibrational entropy of association is always favorable, especially for Arg-Ade and Asn/Gln-Ade due to the shape of the complexes, (iii) the calculated interaction free energies are solvent-dependent and usually negative, especially for Arg-Ade, (iv) and they are consistent with the frequencies of cation-π pairs observed in the dataset.
Arg-, Lys- and Asn/Gln-Ade pairs which display mimimal interaction free energies in water. Carbon atoms are colored in green, oxygen in red and nitrogen in blue. Conolly surfaces are represented by a transluscent solid. The images were generated using Molekel.
1Ingénierie Moléculaire et Biomoléculaire