Simulation-guided design of peptide–metal coordination interfaces for next-generation metallo-immunotherapy

The therapeutic application of metal ions in cancer immunotherapy is constrained by systemic toxicity and challenges in spatiotemporal control. Peptide-metal coordination interfaces present a programmable strategy to address these limitations, leveraging sequence-encoded recognition and tunable coordination chemistry to achieve controlled metal speciation, bioavailability, and stimulus-responsive functionalities within complex biological systems. This research direction explores the mechanisms by which essential metal ions, such as Mn2+, Zn2+, Cu2+, and Fe2+/Fe3+, influence both innate and adaptive immune responses through direct modulation of immune cells and indirect remodeling of the tumor microenvironment, including immunogenic cell death and redox perturbation. The project focuses on the design principles of peptide-metal coordination, encompassing natural binding motifs and

synthetic coordination primitives. A simulation-guided computational framework is proposed, integrating docking for initial screening, molecular dynamics and metadynamics for stability evaluation, quantum mechanical/molecular mechanics for precise electronic-level analysis, and machine learning for multi-parameter optimization. This comprehensive approach aims to facilitate the rational discovery and design of advanced peptide-metal platforms for next-generation metallo-immunotherapy.

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