Comparative study of interaction energies between αIIbβ3 integrin and the peptidic, peptidomimetic and non-peptidic ligands by quantum mechanics FMO-PIEDA calculations

Abstract

Integrins are one of the major families of cell adhesion receptors. The recognition of the vital roles of integrins in various diseases revealed their therapeutic potential. To better understand an adhesion mechanism of integrins, pair interaction energy decomposition analysis (PIEDA) along the two-body fragmented molecular orbital (FMO) method was used. Interaction energies were evaluated between the amino acid residues including Mg2+ and Ca2+ ions at ligand-binding site of αIIbβ3 integrin and two peptide chains with the Ala-Gly-Asp and the Arg-Gly-Asp binding motifs, a cyclic peptide (eptifibatide), peptidomimetic ligands (tirofiban and L-739758) and poly(L-lactic acid) chain (PLA). The results indicate that Mg2+ and Ca2+ ions together with Asp224A, Asn215B, Asp159A and Lys125B of αIIbβ3 are the most important residues for a binding of the peptidic ligands while for the peptidomimetic ligands and PLA, interactions with Ca2+ ions are less significant than those with amino acid residues of αIIbβ3. For all complexes a dominant part of interaction energy comes from electrostatic interactions. Based on optimized geometries at the quantum mechanics/molecular mechanics (QM/MM) level an interaction pattern predicted for PLA was compared with the native peptidic ligands.