@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 = {

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.

}, 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 {2025, title = {Impact of Multiple Phosphorylations on the Tau-R2/Tubulin Interface.}, journal = {Biochemistry}, volume = {64}, year = {2025}, month = {2025 Jul 01}, pages = {2916-2925}, 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 to 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 phosphorylation 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 mobility of the tubulin disordered C-terminal tails (CTTs). We show how the tubulin CTTs help maintain the tau-R2 fragment on the tubulin surface despite the destabilizing effect induced by phosphorylations. Conversely, tau phosphorylation affects the CTTs\&$\#$39; flexibility and their potential activity as MAP-recruiting hooks. Furthermore, counterion-mediated bridges between the phosphate groups and tubulin glutamates also contribute to the binding of tau-R2 on the MT. Overall, the complex dynamics of this fuzzy phosphorylated assembly shed new light on the importance of the cytoplasmic environment in neurons in the context of Alzheimer\&$\#$39;s disease.

}, keywords = {Humans, Microtubules, Molecular Dynamics Simulation, Phosphorylation, Protein Binding, tau Proteins, Tubulin}, issn = {1520-4995}, doi = {10.1021/acs.biochem.5c00109}, author = {Marien, Jules and Pr{\'e}vost, Chantal and S Sacquin-Mora} } @article {2025|2171, title = {Sticky Salts: Overbinding of Monovalent Cations to Phosphorylations in All-Atom Force Fields.}, journal = {J Chem Inf Model}, year = {2025}, month = {2025 Dec 05}, abstract = {

Phosphorylation is a major post-translational modification that is involved in the regulation of the dynamics and function of intrinsically disordered proteins (IDPs). We recently characterized a phenomenon, which we termed -phosphate collaborations (P-collabs), where bulk cations form stable bridges between several phosphoresidues in all-atom molecular dynamic simulations. P-collabs were found to be sensitive to the combination of force fields and cation types. Here, we attempt to assess the physical relevance of these P-collabs by evaluating the strength of the cation/phosphate interaction through osmotic coefficient (ϕ) calculations on the model 2NaHPO and 2KHPO salts, using different classical force fields for phosphorylations. All force fields were found to overestimate the strength of the interaction to various degrees. We thus designed new parameters for CHARMM36m and AmberFF99SB-ILDN using the Electronic Continuum Correction (ECC) approach, which provide remarkable agreement for ϕ values for both cation types and over a range of concentrations. We provide a preliminary test of these ECC parameters for phosphorylations by simulating the 7-fold-phosphorylated rhodopsin peptide 7PP and comparing secondary chemical shifts to experimental data. Conformational ensembles resulting from the ECC-derived phosphorylated force fields display both qualitative and quantitative improvements with regard to full-charge force fields. We thus conclude that long-lasting P-collabs are artifacts for classical force fields born from the lack of explicit polarization, and propose a possible computational strategy for the extensive parametrization of phosphorylations. The presence of long-lived P-collabs in simulations produced using classical force fields is therefore a serious concern for the accurate modeling of multiphosphorylated peptides and IDPs, which are at the center of research questions regarding neurodegenerative diseases such as Alzheimer\&$\#$39;s or Parkinson\&$\#$39;s.

}, issn = {1549-960X}, doi = {10.1021/acs.jcim.5c02154}, author = {Marien, Jules and Puyo-Fourtine, Julie and Pr{\'e}vost, Chantal and S Sacquin-Mora and Dubou{\'e}-Dijon, Elise} } @article {2024|2167, title = {NP-collabs: Investigating counterion-mediated bridges in the multiply phosphorylated tau-R2 repeat}, journal = {J. Chem. Inf. Model.}, volume = {64}, year = {2024}, pages = {6570{\textendash}6582}, abstract = {

Tau is an intrinsically disordered (IDP) microtubule-associated protein (MAP) that plays a key part in microtubule assembly and organization. The function of tau can be regulated by 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\&$\#$39;s disease. Using all-atom molecular dynamics 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 (FF)/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 (for nphosphate collaboration, with n being an integer), 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 phosphoresidue spacing and ionic concentration by modeling polyalanine peptides containing two phosphoserines located one-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 at the residue level.

}, author = {Marien, Jules and Pr{\'e}vost, Chantal and S Sacquin-Mora} }