Designing Mimosine-Containing Peptides as Efficient Metal Chelators: Insights from Molecular Dynamics and Quantum Calculations

valent and trivalent metal cations, including Zn2+ , Ni2+ , Fe2+∕3+ , and Al3+ . This ability endows mimosine with significant antimicrobial and anti-cancer properties, making it a promising candidate for therapeutic applications. Previous research has demonstrated the effectiveness of mimosine- containing peptides as metal chelators, offering a safer alternative to conventional chelation agents. However, optimizing the design of these peptides necessitates a thorough understanding of their conformational ensembles in both free and metal-bound states. Here, we perform an in-depth analysis of mimosine-containing peptides using long-time MD simulations and quantum calculations to identify key factors critical for peptide design. Our results show that these peptides can achieve metal-binding affinities comparable to established aluminum chelators like deferiprone and citrate. Additionally, we underscore the crucial role of the peptide backbone in reducing the entropic penalty associated with metal binding. We propose strategies to modulate this entropic penalty —a challenging thermodynamic property to evaluate but essential in complexes between short peptides and metals— by incorporating proline residues and optimizing sequence length. These approaches offer promising pathways for developing efficient peptide chelators.