Mapping the Conformational Free-Energy Landscape of Classical Opioid Peptides using Extensive Molecular Dynamics and Bias Exchange Metadynamics Simulations

Abstract

Opioid receptors are members of an important G protein-coupled receptor (GPCR) subfamily and targets for potent, widely used analgesics in the clinic. The main subtypes of this subfamily are the structurally related, highly homologous, mu-opioid (MOP), kappa-opioid (KOP), and delta-opioid (DOP) receptors. Although opioids targeting the MOP receptor have long been employed in clinical pain management, they display several serious adverse effects, including strong physical dependence. Selective DOP receptor agonists have been reported to exhibit strong antinociceptive activity with fewer side effects, making them ideal candidates for a more effective and safer analgesia. Among the most potent agonists of the DOP receptor are the linear and cyclic enkephalin analogs known as DADLE (Tyr-D-Ala-Gly-Phe-D-Leu) and DPDPE (Tyr-D-Pen-Gly-Phe-D-Pen), respectively. The structural properties of these penta-peptides have been studied extensively over the years, using both experimental and computational methods. However, to the best of our knowledge, a thorough examination of the conformational free-energy landscape of DADLE and DPDPE in an explicit solvent is missing from the literature. Here, we employ microsecond-scale molecular dynamics and bias-exchange metadynamics simulations of DADLE and DPDPE in an explicit solvent to provide such a structural and energetic characterization. Our results point to a small number of conformational minima in solution for both DADLE and DPDPE, separated by relatively small energy barriers. Among the different energy minima, putative bioactive conformations are identified based on rigid docking of each energy basin representative into the binding pocket of the newly released crystal structure of the DOP receptor. This information offers an unprecedented opportunity for the structure-based design of potent, selective peptidomimetics for the DOP receptor.