Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers.

The study of tau protein aggregation and interactions with other molecules or solvents using molecular dynamics simulations (MDs) is of interest to many researchers to propose new mechanism-based therapeutics for neurodegenerative diseases such as Alzheimer's disease, Pick's disease, chronic traumatic encephalopathy, and other tauopathies. In this review, we present recent MD simulation studies of tau oligomers and fibrils such as tau-NPK, tau-PHF, tau-K18, and tau-R3-R4 monomers and dimers. All-atom simulations by replica exchange MDs and coarse-grained MDs in lipid bilayers and in solution were used. The simulations revealed different mechanisms in the binding of tau in bilayers and in solutions, depending on the peptide size. Phosphorylation is also an important factor in MD simulations. The use of steered MDs was also included to simulate the dissociation of tau fibrils. The exponential improvement in the computing power of computers has led to an increasing number of scientists and engineers using a cost-effective, high-performance computing platform to study how the tau protein interacts and the effects of changing its structure, such as the phosphorylation of tau fibrils.

Tau fibril with membrane lipids: Insight from computational modeling and simulations.

The microtubule-binding protein tau has been the center of researches concerning Alzheimer's disease (AD) due to several clinical trials of ß-amyloid therapies failing recently. The availability of the tau fibril structure from AD brain enables computational modeling studies to calculate binding affinities with different ligands. In this study, the tau paired helical filaments (PHF-Tau) (PDB ID: 5O3L) was used as receptor and interactions with the lipids: 3-alpha-cholesterol; 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; and C18:1 sphingomyelin, were explored with molecular docking, molecular dynamics, and natural bond orbital analysis. Docking sites upon solvation of the protein with transferable interatomic potential-3 points reveal the amphipathic nature of PHF-Tau and molecular dynamics simulations show that the embedded phosphocholine at the tail side gives high potential energy values with some amino acids forming H-bond interactions.