Impact of multiple phosphorylations on the tau-R2/tubulin interface

This Zenodo repository contains the data for the following article : Impact of multiple phosphorylations on the tau-R2/tubulin interface by Jules Marien, Chantal Prévost and Sophie Sacquin-Mora Abstract : The phosphorylation of the microtubule-associated tau protein plays a key role in the regulation of its physiological function. In particular, tau hyperphosphorylation affects its binding on the tubulin surface, destabilizing the tau-microtubule interface and leading to the accumulation of fibrillar aggregates in the brain. In this work, we performed classical Molecular Dynamics simulations for the tau-R2/tubulin assembly with various phosphorylations states of serines 285, 289 and 293. We analyze the resulting trajectories to obtain a detailed view of the protein interface in the complex, and the impact of tau phosphorylations on the stability of this assembly, and on the tubulin disordered C-Terminal tails (CTTs) mobility. We show how the tubulin CTTs help maintaining the tau-R2 fragment on the tubulin surface despite the destabilizing effect induced by phosphorylations. Conversely, tau phosphorylation affects the CTTs flexibility and their potential activity as MAP recruiting hooks. Furthermore, counterion mediated bridges between the phosphate groups and tubulin glutamates also contribute to the binding of tau-R2 on the MT. Keywords: Molecular Dynamics, protein interactions, tubulin, tau, disordered proteins, phosphorylations Detailed content of the repository : - MD_files : contains the NAMD equilibration and production files necessary to launch the simulations and an example for the colvar restraint on tilt. The toppar/ subdirectory contains the parameter files of the forcefield CHARMM36m used for this study. The following directories contain all-atom molecular dynamics (MD) simulations. Files ending in .log or .out contain the log of the first step of equilibration, including all parameters such as the seed. Files starting by raw_PSF are the topological files of the system, water included. Files starting with raw_PDB_full_trimere are the PDB files containing the starting point of the simulation, water included. Files starting with PDB_protein_ions_trimere are the PDB files containing the starting point of the simulation, water excluded. Files starting with DCD_protein_ions_trimere are the DCD trajectory files containing the simulation, water excluded. The last two types of files still contain the bulk ions wrapped around the tubulin cores or the R2 repeat if it is present, as bulk ions play a significant role in proteic dynamics via nP-collabs [1]. Analysis were performed on PDB_protein_ions_trimere and DCD_protein_ions_trimere files. - Simulations_trimers_with_R2 : contains the MD simulations of the tau-R2 peptide in complex with three tubulins described in the paper. a1_b3 corresponds to the βIII/αI/βIII trimer, alpha1_beta1 corresponds to the βI/αI/βI trimer and without_CTTs corresponds to the trimer with truncated C-terminal tails. Replicas are called by the model number from which they originate as described in [2]. A serine is coded as 0 and a phosphoserine is coded as 1, with order "Ser285_Ser289_Ser293". Example : "1_0_1" means that R2-Ser285 and R2-Ser293 are phosphorylated. - Simulations_trimers_without_R2 : contains the MD simulations of the three tubulins without the tau-R2 peptide described in the paper. a1_b3 corresponds to the βIII/αI/βIII trimer, alpha1_beta1 corresponds to the βI/αI/βI trimer. Replicas are called by the model number from which they originate as described in [2]. References [1] Marien J, Prévost C, Sacquin-Mora S. nP-Collabs: Investigating Counterion-Mediated Bridges in the Multiply Phosphorylated Tau-R2 Repeat. J Chem Inf Model. 2024 Aug 26;64(16):6570-6582. doi: 10.1021/acs.jcim.4c00742. [2] Marien J, Prévost C, Sacquin-Mora S. It Takes Tau to Tango: Investigating the Fuzzy Interaction between the R2-Repeat Domain and Tubulin C-Terminal Tails. Biochemistry. 2023 Aug 15;62(16):2492-2502. doi: 10.1021/acs.biochem.3c00092.