Coarse-Grained Molecular Dynamics Simulations of Molecular Interaction of Human Tau Protein Fragment with Neuronal Membranes

The membrane-binding domain of human tau (K18) belongs to a class of intrinsically disordered proteins (IDPs) that rapidly self-aggregates in solution and on various surfaces. It is believed that the self-aggregation of K18 on neuronal membrane surfaces is responsible for the early progression of Alzheimer's disease. Currently, the molecular details of protein-protein and protein-lipid interactions of K18 aggregates on neuronal membranes are unknown. Using coarse-grained MD simulations, we have investigated the molecular interactions of various sizes of K18 aggregates on phase-separated lipid nanodomains up to tens of microseconds. We have constructed neutral and negatively charged lipid domains containing phospholipid, glycolipid, and cholesterol that mimic both the inner and outer leaflets of neuronal membranes. From the simulation data, we have determined the binding preferences of K18 among the phase-separated liquid-ordered and liquid-disordered lipid domains, as well as the binding energies of protein-protein and protein-lipid interactions. This work improves our understanding of IDP interactions on nanostructured surfaces, as well as the future design of anti-aggregation drugs and treatment for neurodegenerative diseases.