L-DOPA and Droxidopa: From Force Field Development to Molecular Docking into Human β2-Adrenergic Receptor

Abstract

The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to β2-adrenergic receptor (β2AR) inactive and active states has led us to investigate protein–ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human β2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible β2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into β2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 μs MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF.