Biology subjects

Bhargava, B. L.

Publications and source records attributed to Bhargava, B. L..

3 recordsLinked to original sources

bioRxiv2023

Phosphatidylinositol (PI) Lipids Modulate the Binding of Tau Fibrils on Lipid Bilayers

Phosphatidylinositol (PI) lipids play a crucial role as a vital lipid component in cell membrane domain formation, contributing to cell signaling. In this study, we investigate the impact of PI lipids on the conformational dynamics of tubulin-associated unit (tau) fibrils through multiscale modelling. While prior experimental work by the Lecomte group has demonstrated the influence of PI lipids on the morphology and secondary structure of tau fragments, a detailed molecular understanding of the binding mechanism between tau and PI-incorporated lipids remains absent. Our molecular dynamics (MD) simulations reveal the intricate molecular mechanisms governing tau binding to PI-incorporated bilayers. Specifically, we conduct MD simulations on lipid patches containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (PC) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (PG), enabling us to explore conformational changes in the R3-R4 section of tau fibrils. Control simulations are conducted on pure lipid patches without tau fibrils, as well as on tau fibrils within bulk water. Our findings demonstrate that PI-incorporated lipids exhibit a stronger affinity for binding to tau fibrils compared to pure PC/PG lipids. All-atom simulations highlight the potential docking sites for PI headgroups at positively charged residues (Lysine, Arginine) on the tau surface. Moreover, the aggregation of PI lipids facilitates tau binding to the membrane. These results not only enhance our comprehension of the disruption of PI-incorporated bilayers, but also shed light on the stability of the tau over the PI containing bilayers.

biophysics↗

bioRxiv2022

Interaction of the Tau fibrils with the neuronal membrane

Tau proteins are gaining a lot of interest recently due to their active role in causing a range of tauopathies. Molecular mechanisms underlying the tau interaction with the neuronal membrane are hitherto unknown and difficult to characterize using conventional experimental methods. Starting from the cryo-EM structure of the tau fibrils, we have used atomistic molecular dynamics simulations to model the interaction between the fibril and neuronal membrane, with explicit solvation. The dynamics and structural characteristics of the tau fibril with the neuronal membrane are compared to the tau fibril in the aqueous phase to corroborate the effect of the neuronal membrane on the tau structure. The tau fibrils are in general more compact in the presence of neuronal membrane compared to their structure in the water medium. We find that the number of {beta} -sheet residues of the tau fibrils are different in the case of two polymorphs, paired helical filament and straight filaments (PHF and SF) in the two media. PHF is found to approach closer to the neuronal membrane than the SF. The negatively charged lipids in the neuronal membrane are found to mediate the tau-neuronal membrane binding. Our study initiates the understanding of tau conformational ensemble in the presence of neuronal membrane and sheds light on the significant tau - membrane interactions. The simulation times of our report might limit the conformational sampling required to observe membrane permeation, nevertheless it provides significant insights into fibril - neuronal membrane interactions.

biophysics↗

bioRxiv2022

The Effect of Lipid Composition on the Dynamics of Tau Fibrils

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 effect 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 affinity of the tau fibrils. The addition of cholesterol is also found to modify the tau binding to the membrane.

biophysics↗