Use multiscale simulation to explore the effects of the homodimerizations between different conformation states on the activation and allosteric pathway for the μ-opioid receptor

• DOI: 10.1039/c8cp02016g
• Publication Date: 2018-04-19T15:33:52Z
• Authors: Xi Zhang; Yuan Yuan; Longrong Wang; Yanzhi Guo; Menglong Li; Chuan Li; Xuemei Pu
• Keywords: Mice; Protein Subunits; 0303 health sciences; 03 medical and health sciences; Allosteric Regulation; Protein Conformation; Receptors, Opioid, mu; Animals; Molecular Dynamics Simulation; Protein Multimerization; Protein Binding; Signal Transduction

Recently, oligomers of G-protein coupled receptors (GPCRs) have been an important topic in the GPCR fields. However, knowledge about their structures and activation mechanisms is very limited due to absence crystal reported. In this work, we used multiscale simulations study effects homodimerization between different conformation states on activation, dynamic behaviors, allosteric communication pathways for μ-OR. The results indicated that dimerization one inactive monomer with either or active could enhance its constitutive activation. state other protomer (e.g., inactive) can influence activated extent. two protomers leads a negative cooperativity which should contribute asymmetric dimers observed some experiments. On hand, monomer, receptor alleviate deactivation, whereby positive cooperativities be subunits dimer, depending regions. Observations from protein structure network (PSN) analysis would cause significant drop number main ligand binding pocket region protomer, while impact minor protomer. But, one, significantly change types residues participating pathway highest frequency.