Investigating the Role of Charge-Altering Post-Translational Modifications on Tau Peptide Conformational Ensembles using Polarizable Molecular Dynamics Simulations

Aggregation of amyloidogenic proteins, such as the amyloid β-peptide, microtubule-binding protein tau, and α-synuclein, is linked to a number of human diseases. Amyloidogenic proteins unfold, aggregate, and self-assemble into highly stable, insoluble fibrils characterized by cross-β structure. Despite having unique primary sequences, these amyloidogenic proteins all undergo similar conformational changes, from disordered and only partially structured, to highly ordered in the fibril form. The forces driving such changes in structure are not completely characterized and a better understanding is needed to potentially combat a wide range of diseases that are currently incurable. In this study, we performed molecular dynamics simulations with the Drude polarizable protein force field to gain a better understanding of protein aggregation. We previously found that the explicit representation of electronic polarization was required to delineate mutation-specific unfolding pathways of the amyloid β-peptide. Building upon those findings, here we explore the impact of charge-altering post-translational modifications (PTMs) on the dynamics of tau, the protein that forms intracellular, neurofibrillary tangles in Alzheimer's disease. PTMs like acetylation of lysine and phosphorylation of serine and threonine are known to induce tau aggregation, but the underlying molecular mechanism remains unknown. By studying fragments of tau harboring these PTMs, we sought to gain novel insights into how changes in charge caused by PTMs shift the conformational ensembles of fragments of the tau protein. Polarizable simulations of these charge-altering PTMs shed light on how electrostatic interactions, including those between permanent and induced dipoles, affect side-chain properties, salt bridges, water and ion interactions, and changes in secondary structure