Résumé :
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Dystrophin is a long filamentous protein, its central region is made by 24 successive spectrin-like repeats structured in a coiled-coil (bundle of three alpha-helices) arrangement [1]. Its biological function is essential for keeping the integrity of the sarcolemma upon the contraction-relaxation cycles of muscle cells. Lack of dystrophin induces the lethal Duchenne muscular dystrophy genetic disease.Homology models for dystrophin fragments have been obtained from spectrin repeats used as structural patterns [2]. These models revealed highly diverse surface properties of the repeats and to further characterise them, the aim of this work was to study the mechanical and vibrational properties of two sub-domains of the dystrophin rod domain by molecular dynamics. We focused on both N-term and C-term extremity fragments of the dystrophin central rod domain, mainly because these regions (repeats R1 to R3 and R20 to R24) constitute structurally independent sub-domains as they are flanked by hinges. In addition, they present clear different biophysical properties, such as their lipid-binding affinity and thermal stability.Molecular Dynamics (MD) simulations performed in solution at both atomistic and "coarse-grain" (MARTINI forcefield) resolutions bring complementary views of the behaviour of these two independent parts of the long coiled-coil protein filament dystrophin. With this multi-scale simulation approach, we characterize dynamical and mechanical properties and propose a complete mapping of the physico-chemical characteristics revealed by the MD relaxed models. [1] E. Le Rumeur, S.J. Winder and J.-F. Hubert, Dystrophin : more than just the sum of its parts , Biochim. Biophys. Acta 1804, 1713-22 (2010)[2] B. Legrand, E. Giudice, A. Nicolas, O. Delalande and E. Le Rumeur, Computational Study of the Human Dystrophin Repeats: Interaction Properties and Molecular Dynamics, (submitted)
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