Structural and Energetic Characterization of the TmGpx1–CK2β Complex Using Molecular Dynamics Simulations

Information from the abstract

Talaromyces marneffei is a dimorphic fungal pathogen that survives within host macrophages by counteracting oxidative and immune stress. Recently, several host macrophage proteins interacting with the antigenic T. marneffei glutathione peroxidase TmGpx1 were identified. Among these candidate proteins, the regulatory subunit of casein kinase 2, CK2β (CSNK2B), was selected for structural modeling and molecular dynamics simulations to investigate the molecular basis of the host-pathogen interaction. Our findings also suggest a previously unrecognized role for fungal glutathione peroxidase in modulating host cytoskeleton regulation. Here, we used an AlphaFold3-based structure prediction and molecular dynamics simulations to characterize and evaluate the TmGpx1–CK2β interaction. The complex remained stably associated throughout the 200 ns simulations, with sustained intermolecular proximity, extensive heavy-atom contacts, and a persistent hydrogen-bond network. MM/GBSA calculations indicated a favorable total binding energy (−58.17 ± 13.13 kcal/mol), driven mainly by van der Waals and electrostatic contributions. Two contact pairs, TmGpx1 Arg128–CK2β Trp12 and TmGpx1 Val126–CK2β Glu73, were conserved across all three replicates and coincided with the residues contributing most favorably to binding energy. Notably, TmGpx1 Leu123, Leu124, and Val126—residues previously implicated in the TmGpx1–FKBP15 interaction—recurred at the CK2β interface, and the TmGpx1 catalytic triad (Cys39, Gln76, Trp131) was also engaged in CK2β binding. These findings support a stable and energetically favorable TmGpx1–CK2β interface and suggest that TmGpx1 recognizes multiple host regulatory proteins through a shared interaction surface that may be functionally linked to its catalytic activity.

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Related topics: Protein Structure and Dynamics · Fungal Infections and Studies · Computational Drug Discovery Methods