Fig. 4: Structure-informed mechanism for EGCG-driven disaggregation of AD-tau PHF.

Solvation energy calculations of tau PHF structures without EGCG (a) and with EGCG after 3-h incubation (b). Red residues are more stable; blue residues are less stable. The most stable residues seen across both structures are hydrophobic and buried within the fibril core, and less stable residues are typically on the solvent-exposed surface. At 3-h incubation, the structure is less stable (−28.1 kcal/mol/chain) than without EGCG (−34.9 kcal/mol/chain). c To understand the localized effects in fibril stability, energy difference maps were calculated. Subtraction of the no-EGCG model from the 3-h EGCG model shows a large increase in free energy of Lys340 at the EGCG binding site, indicating the presence of EGCG significantly destabilizes Lys340. d The 3-h PHF-EGCG structure reveals EGCG molecules stacked 4.8 Å apart, permitting each EGCG molecule to H-bond with individual stacked molecules of tau (dashed yellow lines connecting EGCG to tau side chains Asn327 and His329). The 4.8 Å spacing between tau molecules is characteristic of the intermolecular β-sheet hydrogen bonding distance (dashed yellow lines connecting tau molecules). However, this 4.8 Å spacing incurs unfavorable voids between EGCG rings A, C, and D (as indicated by gaps between space-filling atoms). e The voids between stacked aromatic groups can be filled by compressing the distance between these A, C, and D aromatic rings that face the solvent. In so doing, the EGCG stack curves, widening the spacing on the fibril-facing surface. Asn327 and His329 can maintain favorable hydrogen bonding with the curved stack of EGCG molecules only if the tau molecules separate wider than 4.8 Å. This separation would allow water to solvate the separated tau molecules. The curvature of the EGCG stack fills the unfavorable voids between EGCG aromatic rings and further widens the separation between tau molecules. By this mechanism, the binding energy between stacked EGCG molecules is converted to a conformational change that pries apart stacked tau molecules. f Alternate view showing a tau PHF protofilament being disrupted by the curvature of stacked EGCG molecules. g Reaction coordinate diagram describing the possible mechanism of tau disaggregation by EGCG. Tau PHFs in solution with EGCG (coordinate A) are bound by repeating stacks of EGCG molecules (coordinate B). Once EGCG is bound, local charge-mediated effects begin to destabilize the fibril (coordinate C). These effects include unfavorable burying of charged residues (e.g. Lys340) and disruption of pairing between charged side chains. These repulsive forces, in addition to possible backbone H-bonding between tau and EGCG, weaken the β-sheet H-bond network of the fibril. Lastly, conformational changes induced by EGCG π-π stacking (described in d–f) may further disrupt the fibril architecture (coordinate D), leading to the disaggregated EGCG-bound tau end product (coordinate E).