Homology Modeling and Molecular Dynamics Simulations of the Mu Opioid Receptor in a Membrane–Aqueous System

Abstract

Three types of opioid receptors-mu, delta, and kappa-belong to the rhodopsin subfamily in the G protein-coupled receptor superfamily. With the recent characterization of the high-resolution X-ray crystal structure of bovine rhodopsin, considerable attention has been focused on molecular modeling of these transmembrane proteins. In this study, a homology model of the mu opioid receptor was constructed based on the X-ray crystal structure of bovine rhodopsin. A phospholipid bilayer was built around the receptor, and two water layers were placed on both surfaces of the lipid bilayer. Molecular-dynamics simulations were carried out by using CHARMM for the entire system, which consisted of 316 amino acid residues, 92 phospholipid molecules, 8327 water molecules, and 11 chloride counter ions-40 931 atoms altogether. The whole system was equilibrated for 250 ps followed by another 2 ns dynamic simulation. The opioid ligand naltrexone was docked into the optimized model, and the critical amino acid residues for binding were identified. The mu opioid receptor homology model optimized in a complete membrane-aqueous system should provide a good starting point for further characterization of the binding modes for opioid ligands. Furthermore, the method developed herein will be applicable to molecular model building to other opioid receptors as well as other GPCRs.

Molecular Dynamics Simulations of Na+/Cl−‐Dependent Neurotransmitter Transporters in a Membrane‐Aqueous System

“…[32] Such an approach has for instance been applied for the optimization of GPCR receptor homology models in membranes or simplified membrane systems. [33][34][35][36][37] The literature provides numerous examples of molecular dynamics (MD) simulation studies of membrane proteins in explicit lipid bilayers, [38][39][40][41][42][43][44] simplified membrane-water systems, such as the octane slab developed by Sansom's lab, [43,45] and uniform solvent dielectric models. [46] Performing MD simulations of membrane proteins in explicit bilayer systems is an often applied approach to study membrane proteins.…”

Mutations in the Amino Terminus of Herpes Simplex Virus Type 1 gL Can Reduce Cell-Cell Fusion without Affecting gH/gL Trafficking

“…To better rationalize the effects of the substitution mutations based on their specific locations on the protein structure, we constructed a homology model of the HSV-1 gH/gL (NCBI accession numbers NP_044623 for gH and NP_044602 for gL) based on the X-ray structure of HSV-2 gH/gL (16), by using previously described methods (24,25). The modeling was done using the Prime module of the Schrodinger modeling package.…”

GPCRHomology Model Development and Application

“…While it is far from routine, the receptor model may also be simulated in the presence of lipid bilayer. Applying this to the mu-opioid receptor [70], for example, shows the TM bundle to become more compact, with implications for the binding site.…”