Fig. 5: Aromatic stacking interactions in the Tau-5_{R2_R3}:EPI-002 and Tau-5_{R2_R3}:EPI-7170 bound ensembles.

A Populations of aromatic stacking contacts between aromatic sidechains of Tau-5_{R2_R3} and aromatic rings of EPI-002 and EPI-7170 were observed in the 300 K replica of explicit solvent REST2 MD simulations. Populations are presented as mean values ± statistical error estimates from blocking. B Definition of angles and distances used to define stacking orientations and examples of parallel stacked and T-stacked conformations between EPI compounds and a tyrosine sidechain. For a protein aromatic ring and a ligand aromatic ring, R is defined as the distance between ring centers, \(\hat{R}\) is defined as the unit vector connecting the ring centers, \(\hat{n}\)_protein and \(\hat{n}\)_ligand are normal vectors to the sidechain and ligand ring planes originating from the ring centers, θ is the angle between \(\hat{n}\)_protein and \(\hat{n}\)_ligand, and ϕ is the angle between \(\hat{n}\)_protein and \(\hat{R}\). Parallel stacked conformations are defined as occurring when R < 6.5 Å, θ < 45°, & ϕ <60° and T-stacked conformations are defined as occurring when R < 7.5 Å, θ > 75°, & ϕ <60°. C Free energy surfaces as a function of R and θ between the chlorinated phenyl ring of EPI-7170 and the equivalent non-chlorinated phenyl ring in EPI-002 and the indole rings of TYR 397 and TYR 433. Source data are provided as a Source Data file.