ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Comparative study of interaction energies between α_IIbβ₃ integrin and the peptidic, peptidomimetic and non-peptidic ligands by quantum mechanics FMO-PIEDA calculations

Juraj Kóňa

Medical Vision, Civic Research Association, Bratislava, Slovakia

E-mail: chemkona@savba.sk

Received: 23 March 2023  Accepted: 31 May 2023

Abstract:

Integrins belong to a family of cell adhesion receptors. To better understand an adhesion mechanism of integrins, fragmented molecular orbital (FMO) method with pair interaction energy decomposition analysis (PIEDA) was applied for integrin:ligand complexes. Interaction energies were evaluated between the amino acid residues including Mg²⁺ and Ca²⁺ ions at ligand-binding site of α_IIbβ₃ integrin and two peptide chains with the Ala-Gly-Asp (AGD)- and the Arg-Gly-Asp (RGD)-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 α_IIbβ₃ 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 α_IIbβ₃. For all complexes, a dominant part of interaction energy comes from electrostatic interactions. New developed antagonists of α_IIbβ₃ should mimic not only the interactions of the RGD motif but also the interactions of the backbone of a longer peptidic sequence (RGDV or AGDV) with the focus on the interactions of the antagonists with the ADMIDAS Ca²⁺ ion. An interaction pattern predicted for PLA was compared with the native peptidic ligands.

Keywords: Integrins; Binding mechanism; Polylactic acid; QM/MM calculations; FMO-PIEDA analysis

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-023-02910-4

Chemical Papers 77 (10) 5913–5930 (2023)