Hetero-oligomers in solution and binding to the raft membrane

Description

Disruptions of cell membranes by tau and amylin oligomers are linked to Alzheimer's and Type 2 diabetics, respectively. Recent studies suggest that misfolded tau and amylin can form neurotoxic hetero-tau-amylin oligomers that are structurally different from the homo-oligomers. We have designed and created hetero-tau-amylin oligomers of different sizes using microsecond-resolved coarse-grained MD simulations. In addition, we have modeled the protein binding events of these hetero-oligomers to phase-separated lipid nanodomains (CO-raft) containing saturated phosphatidylcholine (PC), unsaturated PC, and cholesterol. The CO-raft contains the saturated PC- and cholesterol-enriched Lo domain, the unsaturated PC- and cholesterol-depleted Ld domain, and the boundary Lod domain. By adding an anionic lipid, phosphatidylserine (PS) or ganglioside (GM1), to one lipid leaflet of the CO-raft, an asymmetric PS-raft or GM-raft was also created. The PS- and GM1-clusters on the asymmetric PS- and GM-rafts are located mainly in the Lo domain. These PS- and GM1-clusters are physiologically important for signal processing, protein docking, and protein-sorting to maintain the normal functions of the neurons. However, those clusters are also the major cellular targets of misfolded amyloid aggregates on neuronal membranes linking to the onset of Alzheimer's. Video S1: The self-assembling process of the hetero-dimer from one tau monomer and one amylin monomer (Time: 0-5 microseconds). Video S2: The self-assembling process of the heter-tetramer from two tau monomers and two amylin monomers (Time: 0-5 microseconds). Video S3: Binding of hetero-dimer to the CO-raft (lateral view, Time: 0-15 microseconds). Video S4: Binding of hetero-dimer to the CO-raft (transverse view, Time: 0-15 microseconds). Video S5: Binding of hetero-dimer to the PS-raft (lateral view, Time: 0-15 microseconds). Video S6: Binding of hetero-dimer to the PS-raft (transverse view, Time: 0-15 microseconds). Video S7: Binding of hetero-dimer to the GM-raft (lateral view, Time: 0-15 microseconds). Video S8: Binding of hetero-dimer to the GM-raft (transverse view, Time: 0-15 microseconds). Our results provide new molecular insights into understanding the membrane damage mechanisms of hetero-tau-amylin-oligomer associated with the cross-talk between amyloid diseases.

Steps to reproduce

All simulations were performed using GROMACS 4.6.7 based on the Martini 2.2 force fields. Details of the simulations can be found in Santo et al., Macromol 2023, 3, 805-828 (https://www.mdpi.com/2673-6209/3/4/46)

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