1. State transitions of coupled G i -protein: Insights into internal water channel dynamics within dopamine receptor D3 from in silico submolecular analyses.
- Author
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Hsu HJ, Li YT, Lai XY, Yeh YC, Hu TY, and Chang CC
- Subjects
- Protein Binding, Humans, Protein Conformation, Guanosine Triphosphate metabolism, Guanosine Triphosphate chemistry, Molecular Dynamics Simulation, Receptors, Dopamine D3 metabolism, Receptors, Dopamine D3 chemistry, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, GTP-Binding Protein alpha Subunits, Gi-Go chemistry, Water chemistry
- Abstract
Dopamine is a crucial neurotransmitter in the central nervous system (CNS) that facilitates communication among neurons. Activation of dopamine receptors in the CNS regulates key functions such as movement, cognition, and emotion. Disruption of these receptors can result in severe neurological diseases. Although recent research has elucidated the structure of D3R in complex with G
i -protein, revealing the binding and activation mechanisms, the precise conformational changes induced by G-protein activation and GDP/GTP exchange remain unclear. In this study, atomic-level long-term molecular dynamics (MD) simulations were employed to investigate the dynamics of D3R in complex with different states of Gi -protein and β-arrestin. Our simulations revealed distinct molecular switches within D3R and fluctuations in the distance between Ras and helical domains of G-protein across different G-protein-D3R states. Notably, the D3R-GTP-Gi state exhibited increased activity compared with the D3R-empty-Gi state. Additionally, analyses of potential of mean force (PMF) and free energy landscapes for various systems revealed the formation of a continuous water channel exclusively in the D3R-Gi -GTP state. Furthermore, allosteric communication pathways were proposed for active D3R bound to Gi -protein. This study offers insights into the activation mechanism when Gi -protein interacts with active D3R, potentially aiding in developing selective drugs targeting the dopaminergic system., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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