@article {2025|2170,
	title = {Across (Conformational) Space and (Relaxation) Time: Using Coarse-Grain Simulations to Probe the Intra- and Interdomain Dynamics of the Tau Protein.},
	journal = {J Phys Chem B},
	volume = {129},
	year = {2025},
	month = {2025 Nov 27},
	pages = {12146-12158},
	abstract = {<p>The biological importance of intrinsically disordered proteins (IDPs) has been established for over two decades, yet these systems remain difficult to characterize, as they are better described by conformational ensembles instead of a single reference structure for their folded counterparts. Tau is a prominent member of the IDP family, which sees its cellular function regulated by multiple phosphorylation sites and whose hyperphosphorylation is involved in neurodegenerative diseases such as Alzheimer\&$\#$39;s. We used coarse-grain MD simulations with the CALVADOS model to investigate the conformational landscape of tau without and with phosphorylations. Characterizing the local compactness of IDPs allows us to highlight how disorder comes in various flavors, as we can define different domains along the tau sequence. We define the IDP\&$\#$39;s Statistical Tertiary Organization (STO) as the average spatial arrangements of domains, which constitute an extension of the tertiary structure of folded proteins. We also use IDP-specific metrics to characterize the local curvature and flexibility of tau. Comparing the local flexibilities with T2 relaxation times from NMR experiments, we show how this metric is related to the protein dynamics. A curvature and flexibility pattern in the repeat domains can also be connected to tau binding properties, without having to explicitly model the protein\&$\#$39;s interaction partner. Finally, we rediscuss the original paperclip model that describes the spatial organization of tau and how phosphorylations impact it. The resulting changes in the protein intradomain and interdomain interaction pattern allow us to propose experimental setups to test our hypothesis.</p>
},
	keywords = {Humans, Intrinsically Disordered Proteins, Molecular Dynamics Simulation, Phosphorylation, Protein Conformation, Protein Domains, tau Proteins},
	issn = {1520-5207},
	doi = {10.1021/acs.jpcb.5c06282},
	author = {Marien, Jules and Pr{\'e}vost, Chantal and S Sacquin-Mora}
}
@article {2018|2093,
	title = {Dystrophin{\textquoteright}s central domain forms a complex filament that becomes disorganized by in-frame deletions.},
	journal = {J Biol Chem},
	volume = {293},
	year = {2018},
	month = {2018 05 04},
	pages = {6637-6646},
	abstract = {<p>Dystrophin, encoded by the gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophin\&$\#$39;s central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45-47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD.</p>
},
	keywords = {Binding Sites, Dystrophin, Exons, Gene Deletion, Humans, Molecular Docking Simulation, Muscular Dystrophy, Duchenne, Nitric Oxide Synthase Type I, Protein Domains, Reading Frames, Scattering, Small Angle, Solutions, X-Ray Diffraction},
	issn = {1083-351X},
	doi = {10.1074/jbc.M117.809798},
	author = {Delalande, Olivier and Molza, Anne-Elisabeth and Dos Santos Morais, Raphael and Ch{\'e}ron, Ang{\'e}lique and Pollet, {\'E}meline and Raguenes-Nicol, C{\'e}line and Tascon, Christophe and Giudice, Emmanuel and Guilbaud, Marine and Nicolas, Aur{\'e}lie and Bondon, Arnaud and Leturcq, France and Nicolas F{\'e}rey and Marc Baaden and Perez, Javier and Roblin, Pierre and Pi{\'e}tri-Rouxel, France and Hubert, Jean-Fran{\c c}ois and Czjzek, Mirjam and Le Rumeur, Elisabeth}
}
