Across (conformational) space and (relaxation) time: using coarse-grain simulations to probe the intra- and interdomain dynamics of the Tau protein

This repository contains the files and data associated to the article :Across (conformational) space and (relaxation) time: using coarse-grain simulations to probe the intra- and interdomain dynamics of the Tau protein by Jules Marien, Chantal Prévost, and Sophie Sacquin-MoraLaboratoire de Biochimie Théorique, Université Paris-Cité, CNRS, 75005 Paris, France. Experimental data originates from publication "Magnetic resonance investigation of conformational responses of tau protein to specific phosphorylation" by Lasorsa et al in Biophysical Chemistry (2024) [1], and were collected by Dr. Alessia Lasorsa under the supervision of Dr. Isabelle Landrieu. DESCRIPTION : - Dataset_chemical_shifts : contains the dataset with the chemical shifts (CS) computed from the monomeric backmapped simulations of Tau mutant monomers using the SPARTA+ program [2] (denoted "CS sparta (H)" and "CS sparta (N)"), and the experimental chemical shifts measured in [1] (denoted "CS (H)" and "CS (N)"). - Datasets_comparison_T2_LFs_with_and_without_phosphorylations : contains the datasets for the unphosphorylated Tau mutant and the ERK-phosphorylated Tau mutant described in [1]. The values for T2 and standard deviations on T2 were kindly provided by Dr. Alissa Lasorda and Dr. Isabelle Landrieu. Computation of the other quantities is described in the article - Original_data_from_Lasorsa_et_al : contains the original T1, T2 and CS data for the unphosphorylated Tau mutant the ERK-phosphorylated Tau mutant published in [1]. - Simulations : - Dimers : contains the dimeric simulations of the unphosphorylated Tau mutant and the ERK-phosphorylated Tau mutant. Simulations were performed using the CALVADOS package [3] and the Rauh et al phosphoparameters [4]. Two copies of the molecule with charged termini and neutral histidins were placed in a periodic cubic box of sidelength 20nm. The simulations were performed at 278K, at a ionic strength of 0.08 M and pH=7.0 to match experimental data. Simulations were equilibrated for 200000 steps. Production lasted for 2µs with frame collection every 5000 steps. Analyses were performed using file top.pdb as a topology and traj_final.dcd as a trajectory. - Monomers : - 0_pCALVADOS_simulations : coarse-grained CALVADOS simulations were run for monomers using the pCALVADOS notebook developed in [5] with the same parameters as for the dimers, with the exception of the equilibration and production times which were halved. The Tau_ERK2_AT8_mutant simulation was run with the pCALVADOS forcefield, consisting in the combination of the CALVADOS v2 forcefield with adapted phosphoparameters from Perdikari et al [6]. The Tau_ERK2_AT8_mutant_KLL_phosphoparameters simulation was run with the Rauh et al phosphoparameters [4]. Final coarse-grained simulations can be found at Simu_pCALVADOS_Tau_mutant_[]_IDRLab/SIMULATION/top.pdb for the topology and Simu_pCALVADOS_Tau_mutant_[]_IDRLab/SIMULATION/traj.dcd for the trajectory - 1_Postprocessing_AA_2_CG : coarse-grained CALVADOS simulations were backmapped to all-atom using the PULCHRA software [7]. Phosphorylations were then added using a TCL script in VMD [8]. A minimization of the side-chains was then performed using NAMD [9] and the forcefield CHARMM36m [10] to reduce sterical clashes, notably for the phosphorylations. In each case, analyses were performed using file 0_Add_phosphates_and_hydrogenes/Trajectory/topology_minimized_all_atoms_[]_renumbered.psf as a topology and file 0_Add_phosphates_and_hydrogenes/Trajectory/trajectory_minimized_all_atoms_[].dcd as a trajectory. REFERENCES : [1] Lasorsa A, Merzougui H, Cantrelle FX, Sicoli G, Dupré E, Hanoulle X, Belle V, Smet-Nocca C, Landrieu I. Magnetic resonance investigation of conformational responses of tau protein to specific phosphorylation. Biophys Chem. 2024 Feb;305:107155. doi: 10.1016/j.bpc.2023.107155. [2] Shen Y, Bax A. SPARTA+: a modest improvement in empirical NMR chemical shift prediction by means of an artificial neural network. J Biomol NMR. 2010 Sep;48(1):13-22. doi: 10.1007/s10858-010-9433-9. [3] Sören von Bülow, Ikki Yasuda, Fan Cao, Thea K. Schulze, Anna Ida Trolle, Arriën Symon Rauh, Ramon Crehuet, Kresten Lindorff-Larsen, Giulio Tesei. Software package for simulations using the coarse-grained CALVADOS model. arXiv. 2025. doi: 10.48550/arXiv.2504.10408 [4] Arriën Symon Rauh, Gustav Stausbøll Hedemark, Giulio Tesei, Kresten Lindorff-Larsen. A coarse-grained model for simulations of phosphorylated disordered proteins. bioRxiv 2025.03.19.644261. doi 10.1101/2025.03.19.644261 [5] Cynthia Lohberger, Jules Marien, Clarisse Bridot, Chantal Prévost, Diane Allegro, Mario Tatoni, Isabelle Landrieu, Caroline Smet-Nocca, Sophie Sacquin-Mora, Pascale Barbier. Hydrodynamic Radius Determination of Tau and AT8 Phosphorylated Tau Mutants: A Combined Simulation and Experimental Study. bioRxiv 2025.02.22.639620; doi: https://doi.org/10.1101/2025.02.22.639620 [6] Perdikari TM, Jovic N, Dignon GL, Kim YC, Fawzi NL, Mittal J. A predictive coarse-grained model for position-specific effects of post-translational modifications. Biophys J. 2021 Apr 6;120(7):1187-1197. doi: 10.1016/j.bpj.2021.01.034. [7] Rotkiewicz P, Skolnick J. Fast procedure for reconstruction of full-atom protein models from reduced representations. J Comput Chem. 2008 Jul 15;29(9):1460-5. doi: 10.1002/jcc.20906. [8] Humphrey, W., Dalke, A. and Schulten, K., "VMD - Visual Molecular Dynamics", J. Molec. Graphics, 1996, vol. 14, pp. 33-38. [9] James C. Phillips, David J. Hardy, Julio D. C. Maia, John E. Stone, Joao V. Ribeiro, Rafael C. Bernardi, Ronak Buch, Giacomo Fiorin, Jerome Henin, Wei Jiang, Ryan McGreevy, Marcelo C. R. Melo, Brian K. Radak, Robert D. Skeel, Abhishek Singharoy, Yi Wang, Benoit Roux, Aleksei Aksimentiev, Zaida Luthey-Schulten, Laxmikant V. Kale, Klaus Schulten, Christophe Chipot, and Emad Tajkhorshid. Scalable molecular dynamics on CPU and GPU architectures with NAMD. Journal of Chemical Physics, 153:044130, 2020. doi:10.1063/5.0014475 [10] Huang J, Rauscher S, Nawrocki G, Ran T, Feig M, de Groot BL, Grubmüller H, MacKerell AD Jr. CHARMM36m: an improved force field for folded and intrinsically disordered proteins. Nat Methods. 2017 Jan;14(1):71-73. doi: 10.1038/nmeth.4067.