nP-collabs: Investigating counterion mediated bridges in the multiply phosphorylated tau-R2 repeat

Molecular dynamics (MD) simulations without water and general data for the following article : nP-collabs: Investigating counterion mediated bridges in the multiply phosphorylated tau-R2 repeat by Jules Marien, Chantal Prévost, and Sophie Sacquin-Mora Abstract : Tau is an instrinsically disordered (IDP), microtubule-associated protein (MAP) that plays a key part in microtubules assembly and organization. The function of tau can be regulated via multiple phosphorylation sites. These post-translational modifications are known to decrease the binding affinity of tau for microtubules, and abnormal tau phosphorylation patterns are involved in Alzheimer’s disease. Using all-atom molecular dynamics (MD) simulations, we compared the conformational landscapes explored by the tau R2 repeat domain (which comprises a strong tubulin binding site) in its native state and with multiple phosphorylations on the S285, S289 and S293 residues, with four different standard force field/water model combinations. We find that the different parameters used for the phosphate groups (which can be more or less flexible) in these FFs, and the specific interactions between bulk cations and water lead to the formation of a specific type of counterion bridge, termed nP-collab, where counterions form stable structures, binding with two or three phosphate groups simultaneously. The resulting effect of nP-collabs on the tau-R2 conformational space differs when using sodium or potassium cations, and is likely to impact the peptide overall dynamics, and how this MAP interacts with tubulins. We also investigated the effect of phosphoresidues spacing and ionic concentration by modeling polyalanine peptides containing two phosphoserines located one to six residues apart. Three new metrics specifically tailored for IDPs (Proteic Menger Curvature, Local Curvature and Local Flexibility) were introduced, which allow us to fully characterize the impact of nP-collabs on the dynamics of disordered peptides on the residue level. Detailed content of the repository : Zenodo_Marien_nPcollabs.zip : contains the MD simulations (.gro, .tpr, .xtc), the .mdp files, a movie of a 3P-collab formation, the scripts for the Proteic Menger Curvature and the parameters for the nonbonded interactions between cations and phosphate or water oxygens. Zenodo_convergence_simulations.zip : contains the discussion on the convergence of the simulations and the plots for the Block-averaging Standard Error (BSE) and the inter-replica densities for Rg and Ree. Zenodo_DSSP.zip : contains the DSSP plots per replica for the simulations discussed in the article Zenodo_LFs_per_replica.zip : contains the Local Flexibilites (LFs) plots per replica for the simulations discussed in the article