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- Fossépré, Mathieu, et al.
(författare)
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Multiscale design of coarse-grained elastic network-based potentials for the mu opioid receptor
- 2016
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Ingår i: Journal of Molecular Modeling. - : Springer Science and Business Media LLC. - 1610-2940 .- 0948-5023. ; 22:9
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Tidskriftsartikel (refereegranskat)abstract
- Despite progress in computer modeling, most biological processes are still out of reach when using all-atom (AA) models. Coarse-grained (CG) models allow classical molecular dynamics (MD) simulations to be accelerated. Although simplification of spatial resolution at different levels is often investigated, simplification of the CG potential in itself has been less common. CG potentials are often similar to AA potentials. In this work, we consider the design and reliability of purely mechanical CG models of the mu opioid receptor (mu OR), a G protein-coupled receptor (GPCR). In this sense, CG force fields (FF) consist of a set of holonomic constraints guided by an elastic network model (ENM). Even though ENMs are used widely to perform normal mode analysis (NMA), they are not often implemented as a single FF in the context of MD simulations. In this work, various ENM-like potentials were investigated by varying their force constant schemes and connectivity patterns. A method was established to systematically parameterize ENM-like potentials at different spatial resolutions by using AA data. To do so, new descriptors were introduced. The choice of conformation descriptors that also include flexibility information is important for a reliable parameterization of ENMs with different degrees of sensitivity. Hence, ENM-like potentials, with specific parameters, can be sufficient to accurately reproduce AA MD simulations of mu OR at highly coarse-grained resolutions. Therefore, the essence of the flexibility properties of mu OR can be captured with simple models at different CG spatial resolutions, opening the way to mechanical approaches to understanding GPCR functions.
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| 2. |
- Fossépré, Mathieu, et al.
(författare)
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On the Modularity of the Intrinsic Flexibility of the mu Opioid Receptor : A Computational Study
- 2014
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:12, s. e115856-
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Tidskriftsartikel (refereegranskat)abstract
- The mu opioid receptor (mu OR), the principal target to control pain, belongs to the G protein-coupled receptors (GPCRs) family, one of the most highlighted protein families due to their importance as therapeutic targets. The conformational flexibility of GPCRs is one of their essential characteristics as they take part in ligand recognition and subsequent activation or inactivation mechanisms. It is assessed that the intrinsic mechanical properties of the mu OR, more specifically its particular flexibility behavior, would facilitate the accomplishment of specific biological functions, at least in their first steps, even in the absence of a ligand or any chemical species usually present in its biological environment. The study of the mechanical properties of the mu OR would thus bring some indications regarding the highly efficient ability of the mu OR to transduce cellular message. We therefore investigate the intrinsic flexibility of the mu OR in its apo-form using all-atom Molecular Dynamics simulations at the sub-microsecond time scale. We particularly consider the mu OR embedded in a simplified membrane model without specific ions, particular lipids, such as cholesterol moieties, or any other chemical species that could affect the flexibility of the mu OR. Our analyses highlighted an important local effect due to the various bendability of the helices resulting in a diversity of shape and volume sizes adopted by the mu OR binding site. Such property explains why the mu OR can interact with ligands presenting highly diverse structural geometry. By investigating the topology of the mu OR binding site, a conformational global effect is depicted: the correlation between the motional modes of the extra-and intracellular parts of mu OR on one hand, along with a clear rigidity of the central mu OR domain on the other hand. Our results show how the modularity of the mu OR flexibility is related to its preability to activate and to present a basal activity.
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