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Exploring biased activation characteristics by molecular dynamics simulation and machine learning for the μ-opioid
Jianfang Chen1, Qiaoling Gou1, Xin Chen1
1College of Chemistry, Sichuan University, Chengdu 610064, China. xmpuscu@scu.edu.cn.
Physical Chemistry Chemical Physics : PCCP
|March 21, 2024
Summary
Biased ligands offer therapeutic potential but their activation mechanisms are unclear. This study uses molecular dynamics and deep learning to reveal distinct conformational changes in the mu-opioid receptor (μOR) induced by G-protein and β-arrestin biased agonists.
Area of Science:
- Pharmacology and Structural Biology
- Computational Chemistry and Cheminformatics
Background:
- Biased ligands selectively activate specific signaling pathways, offering therapeutic promise.
- Understanding the conformational basis of biased activation is crucial for drug development but remains limited.
- The mu-opioid receptor (μOR) is a key target for pain management, with biased agonists showing potential.
Purpose of the Study:
- To investigate the distinct conformational features of biased activation at the μOR.
- To identify key residues involved in mediating biased signaling by G-protein and β-arrestin agonists.
- To provide insights for the rational design of biased drugs targeting GPCRs.
Main Methods:
- Extensive accelerated molecular dynamics simulations of the inactive μOR with two biased agonists: TRV130 (G-protein biased) and endomorphin2 (β-arrestin biased).
- Application of an interpretable deep learning classification model to analyze simulation data and identify key residues.
- Analysis of ligand binding poses, receptor transmembrane helix movements, and intracellular loop conformations.
Main Results:
- TRV130 binds deeper within the μOR core than endomorphin2, interacting with D114^2.50.
- G-protein biased activation (TRV130) induces greater outward movement of the TM6 intracellular end compared to β-arrestin biased activation (endomorphin2).
- Endomorphin2 causes more significant inward movement of the TM7 intracellular end and complex changes in H8 and ICL1 compared to TRV130; key residues for biased activation were identified by deep learning.
Conclusions:
- Distinct conformational dynamics differentiate G-protein and β-arrestin biased activation at the μOR.
- The study identifies specific residues and structural rearrangements critical for biased signaling.
- These findings offer valuable molecular insights into GPCR biased activation mechanisms, aiding future drug design.
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