Molecular insights into antiamyloidogenic properties of epigallocatechin gallate (EGCG) against zinc-bound β-amyloid using molecular dynamics simulations and Markov state model.

Abstract

In the current study, computational approaches combining molecular docking, quantum mechanical molecular mechanical (QM/MM) calculations, and molecular dynamics (MD) simulations were applied to investigate the binding pattern and associated conformational effects of two EGCG conformers ([Formula: see text] and [Formula: see text]) with [Formula: see text]. Three molecular systems were simulated which were [Formula: see text], and the two complexes, [Formula: see text]-bound [Formula: see text] and [Formula: see text]-bound [Formula: see text], each representing different configuration after the complex formation. [Formula: see text]-bound [Formula: see text] exhibited greater structural stability, compactness, and stronger salt bridge interactions, particularly between Asp23 and Lys28 as observed in the simulation compared to [Formula: see text] and [Formula: see text]-bound [Formula: see text]. In addition, the findings based on Markov state models (MSMs) demonstrated that the binding of [Formula: see text] to [Formula: see text] stabilized the metastable states enriched in helical content, shifting the conformational equilibrium away from β-sheet formation. In contrast, [Formula: see text] binding caused the [Formula: see text] to adopt disordered coil structures while reducing the β-sheet content. Collectively, these results suggested that these two different conformers modulate the metal-induced aggregation and associated conformational landscapes of Aβ via different mechanisms. Furthermore, these results provided rationale for designing small molecule inhibitors that could target metal-induced Aβ aggregation responsible for AD pathogenesis.

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