Structural and mechanistic characterization of heparin interactions with tau fibrils.

Soluble microtubule-associated tau protein can misfold and assemble into stable, insoluble amyloid fibrils. The accumulation of tau amyloid fibrils within neurons is a primary feature in the progression of neurodegenerative diseases, including Alzheimer's disease. Tau fibrils have been observed to colocalize with glycosaminoglycans, such as heparan sulfate (HS), in vivo. Heparin is a highly sulfated analog of HS that has been commonly used in vitro to accelerate tau aggregation. The binding of heparin to tau fibrils inhibits fibril uptake by neighboring cells, whereas HS on the cell surface modulates this uptake. Understanding the molecular interactions of heparin and HS with tau fibrils is important in developing therapeutic targets that can slow the progression of neurodegeneration. In this multiscale computational study, we employ a combination of Brownian dynamics and molecular dynamics to simulate heparin binding to two tau fibril polymorphic structures. Our simulations lead to the de novo prediction of heparin binding to basic residue ladders organized along the tau fibril axis. The mechanism of binding is facilitated by long-range electrostatic steering of the polyanionic heparin to the tau fibril surface, followed by the refinement of favorable short-range heparin-tau interactions. The identified binding sites are located in regions of excess densities in cryo-EM maps of the tau fibrils, providing support for the computational predictions. Our findings provide a structural and mechanistic framework for a better understanding of fibril-glycan interactions and how they influence the overall mechanism of tau fibril propagation.