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

Abstract

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.