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

Abstract

Tau is an instrinsically disordered (IDP), microtubule-associated protein (MAP) that plays a key part in microtubule 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.

Clustering of RNA Polymerase II C-Terminal Domain Models upon Phosphorylation

“…Other computational works on IDPs showed similar observations that counterions mediate the inter- and intra-molecular interactions. 55, 56 All these studies were conducted using AMBER or CHARMM force fields, which have been systematically parameterized and extensively validated against experimental observations 41, 57–59 suggesting their strong ability to provide accurate results for intermolecular interactions. However, in a highly charged concentrated system, the static charges in the standard force fields may have limitations in describing the electrostatics upon the polarization of charged atoms induced by the environment.…”