Galloylation-Driven Anchoring of the Asp325-Asp336 Ridge: The Molecular Logic Behind the Superior Kinetic Stabilization of HMPV Fusion Protein by Green Tea Dimeric Catechins

TL;DR

This study explains how dimeric catechins from green tea stabilize a key viral protein, potentially leading to better antiviral treatments.

Contribution

The study identifies a novel 'Galloylation-Driven Anchoring' mechanism by which dimeric catechins stabilize the HMPV fusion protein.

Findings

The galloyl group of prodelphinidin A2 3′-gallate anchors to an acidic ridge on the HMPV F protein.

This anchoring increases the energy barrier for the virus's fusion process by 9.357 kJ/mol.

Dimeric catechins show superior stabilization compared to monomeric ones due to their structural complexity.

Abstract

The human metapneumovirus (HMPV) Fusion (F) glycoprotein is a high-priority target for “fusion-locking” agents that stabilize its metastable prefusion state. While monomeric catechins like EGCG are known antivirals, the molecular basis for the superior activity of structurally complex dimeric catechins remains poorly understood. We employed an advanced biophysical workflow, integrating 100 ns all-atom molecular dynamics (MD), free energy landscape (FEL) analysis, and MM/GBSA thermodynamic integration to decode the Structure–Dynamics Relationship (SDR) of 210 Camellia sinensis (Green tea) phytochemicals. The results reveal a “Galloylation-Driven Anchoring” mechanism: the galloyl moiety of prodelphinidin A2 3′-gallate provides critical electrostatic complementarity to the Asp325-Asp336 acidic ridge. FEL analysis quantitatively demonstrates that this anchoring leads to pronounced stabilization of the F protein in a deep, kinetically favored global minimum (ΔG = 9.357 kJ/mol), effectively raising the energy barrier for the fusogenic conformational shift. This study provides a comparative and mechanistically informed computational proof-of-concept for the use of dimeric natural scaffolds as precision fusion-locking agents, offering a roadmap for experimental biophysical validation. In this workflow, molecular docking was employed exclusively as a qualitative structure-based filtering step, while all quantitative conclusions regarding stabilization and binding energetics were derived from post-docking MD, FEL, and MM/GBSA analyses.

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