Exploring membrane binding targets of tau oligomers on phase-separated lipid bilayers using multiscale MD simulations.

Abstract

Self-aggregation of tau has been linked to the onset of Alzheimer's. Recent studies indicate that the disordered tau oligomers are more neurotoxic than the ordered tau fibrils in the intracellular neurofibrillary tangle. Details of tau oligomer interactions with the lipid nanodomains in phase-separated lipid bilayers (raft membranes), a model of neuronal membranes, are unknown. Using coarse-grained (CG) and all-atom (AA) MD simulations, a tau-K18 monomer containing the microtubule-binding domain (R1-R2-R3-R4) and its disordered oligomers were simulated. By mixing phosphatidylcholine, cholesterol, ganglioside (GM1), and phosphatidylserine (PS) lipids in water, raft membranes containing lipid nanodomains, liquid-ordered (Lo), liquid-disordered (Ld), and Lo/Ld boundary (Lod) on both lipid leaflets, as well as PS- or GM1-cluster on one lipid leaflet, were simulated. Lipid-binding kinetics and energetics of tau-K18 oligomers to these nanodomains were investigated. Within 20 μs, tau-K18 oligomers bound to the Lod domains in membranes without PS or GM1. In contrast, exclusive binding to PS- or GM1-clusters in membranes containing PS or GM1 occurred in less than 6 μs. After a CG to AA transformation and a 200 ns-AA simulation, disruptions of lipid chain order and beta-sheet formation on raft membranes containing membrane-bound tau-K18 oligomers were found. By mutating three hydrophobic residues to anionic residues at the R2 and R3 domain regions of tau-K18, the mutated tau-K18 oligomers bound much weaker to the PS- or GM1-cluster domains than the wild type did, suggesting the importance of electrostatic interactions in the tau-lipid interactions. Since PS and GM1 are found in the inner and outer leaflets of neuronal membranes, respectively, our results suggest that the PS- and GM1-clusters are leaflet-specific targets while the Lod domains are non-specific targets in membrane-associated tauopathies in Alzheimer's. (Supported by NSF [OAC-153159] and Welch Foundation [W-2057-2021-327].)