Paper Citing NAMD - Abstract
Fossepre, Mathieu; Leherte, Laurence; Laaksonen, Aatto; Vercauteren, Daniel P.
On the Modularity of the Intrinsic Flexibility of the mu Opioid Receptor: A Computational Study
PLOS ONE, 9 Art. No. e115856, DEC 30 2014
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.
