Halogen bonding in biological context: a computational study of D2 dopamine receptor

Abstract

In this work, Halogen Bond (X-bond) interactions formed by halogenated ligands (LX) at the Dopamine Receptor D2 (DRD2) binding pocket were studied by Molecular Dynamics (MD) and charge density analysis. The X-bonds were contrasted with the Hydrogen Bond (H-bond) interactions established by hydroxylated analogs (LOH, where X was replaced by OH). The ligands for this study were extracted from a dataset of compounds deposited in ZINC database that were active in binding assays to DRD2. This dataset was subjected to the filtering rules by employing cheminformatics tools to find the LX/LOH pairs that were then submitted to MD simulations. A homology model of DRD2 was employed for the simulations because no crystal structure is yet available for the receptor. To mimic the positive cap (σ-hole) on the halogen atom, a massless, positive charged extra-point was introduced in the force field. An analysis of the charge density (QTAIM) was performed on reduced models of simulated complexes to explain their binding differences. Results show that the halogen atom tends to form X-bond with protein backbone oxygen atom. Two out of the four halogenated ligands studied form a specific X-bond with the carbonyl oxygen of Ser193. This specific X-bond decreases the inherent propensity of transmembrane 5 to unfolding. These results suggest a possible role of the X-bond as a protein secondary structure modulator because of the ability of the halogen to interact with the protein backbone.