The effect of lipid composition on the dynamics of tau fibrils

Abstract

Knowledge of the interaction of the tau fibrils with the cell membrane is critical for the understanding of the underlying tauopathy pathogenesis. Lipid composition is found to affect the conformational ensemble of the tau fibrils. Using coarse‐grained and all‐atom molecular dynamics simulations we have shown the effect of the lipid composition in modulating the tau structure and dynamics. Molecular dynamics simulations show that tau proteins interact differentially with the zwitterionic compared to the charged lipid membranes. The negatively charged POPG lipid membranes increase the binding propensity of the tau fibrils. The addition of cholesterol is also found to modify the tau binding to the membrane. The binding of tau fibril leads to the concomitant loss of the β‐sheet structures across the tau residues alongside the change in the membrane properties (like area per lipid, bilayer thickness, and order parameter of the lipid tails) over the pure bilayers.

Interaction of the Tau fibrils with the neuronal membrane†

“…We have also calculated the angle of coverage, subtended by the three residues as shown in Figure 2(b). The angle defines the characteristic ‘C’ shape of the PHF and SF structures of tau as shown earlier 17 . The most probable angle of coverage for PHF in the water medium is 53°, and in the neuronal membrane it is 57° with a small distribution at 88°.…”

“…The interaction of the lipid bilayers with the tau is pivotal in understanding the mechanism of toxicity of the tau fibrils 16 . Our earlier MD study was focused on the effect of the net charge of the lipids and the effect of cholesterol in determining the tau conformational changes 17 . It has been widely accepted that the negatively charged lipids influence the tau aggregation 18,19 .…”

Recent Advances in Molecular Dynamics Simulations of Tau Fibrils and Oligomers

“…Bhargava et al studied the tau protein on lipid bilayers by CG MD and AA MD simulations [ 34 ]. The tau-SF structure (PDB ID:5O3T) was modeled with CG using Martini representations [ 35 ] to model the lipids and proteins.…”

“…This shows that MD simulations can be successfully used to study the structure of tau fibrils and the interactions between lipids and other molecules or proteins. As more lipidomic data become available in the literature, the composition of membranes used in simulations can mimic real membrane composition (e.g., neuronal membranes) [ 23 , 33 , 34 , 36 , 37 , 38 , 42 , 45 , 46 , 47 , 51 ]. A major limitation in the previous studies is that most of the computations were performed on a nanosecond time scale, which is due to the computational resources.…”

“…The peptide is shown in a new cartoon representation in blue and the phosphorus atoms are shown as VDW spheres. Adapted with permission from reference [ 34 ]. Copyright (2022), Wiley.…”