Fig. 3: Favorable ligand-ligand interactions support stacked arrangement.

a Comparison of the structure of GTP-1 monomer from an unconstrained DFT optimization (yellow) with the final modeled structure optimized in the context of amyloid-imposed constraints (coral). b Energy decomposition of the GTP-1 stacking interaction in a dimer using an HFLD calculation. c Illustration of the stacked GTP-1 interactions demonstrating the slipped nature of the stack, the retention of the amyloid displacement vector, and the distance of the pi-pi interactions. d Abstracted depiction of how the crossing angle between the plane of the amyloid backbone and the plane of the heterocycle is determined by the amyloid displacement vector and the optimal dimer interaction distance. e The RMSD of the GTP-1 heavy atoms throughout the 100 ns MD simulation, showing the stability of the GTP-1 binding pose. f Representative final frames of a 100-ns MD simulation of tau PHF:GTP-1 (left) and unliganded tau PHF (right) demonstrate both the stability of the GTP-1 binding pose and the complete occlusion of water from the GTP-1 binding site throughout the trajectory.