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<p>The Ru(III) complex, (ImH)[<i>trans</i>-RuCl<sub>4</sub>(DMSO)(Im)](NAMI-A), interacts with histidine(His) and methionine(Met) residues in α-Synuclein due to its unique coordination properties, thereby reducing α-syn’s aggregation-dependent cytotoxicity in neuronal cells and demonstrating promising to alleviate Parkinson’s disease. However, the precise molecular mechanism underlying the coordination of NAMI-A with His and Met residues incompletely elucidated. Herein, the density functional theory (DFT) is used to investigate the binding mechanisms of NAMI-A with two model ligands, N-acetyl-L-methionine (AcMet) and N-acetyl-L-histidine (AcHis). The Gibbs free energies and rate constants indicate that the diaqua hydrolysate of NAMI-A constitutes its pivotal active moiety, wherein the axial water ligand is thermodynamically predisposed to substitution by amino acid residues. Notably, AcMet exhibits a superior binding affinity for Ru(III) in relation to AcHis. Our findings reveal that water ligands are more susceptible to displacement than chloride ligands, underscoring the criticality of the hydrolysis process in the interaction between NAMI-A and biomolecules.</p>

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Structure–activity relationship of NAMI-A interacting with methionine and histidine: a DFT study revealing the critical role of aqua ligand lability in reaction

  • 期刊论文

  • 发表日期：

    2025年11月20日

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  • Wanrong Song,
  • Hui Li,
  • Na Xu

摘要

The Ru(III) complex, (ImH)[trans-RuCl4(DMSO)(Im)](NAMI-A), interacts with histidine(His) and methionine(Met) residues in α-Synuclein due to its unique coordination properties, thereby reducing α-syn’s aggregation-dependent cytotoxicity in neuronal cells and demonstrating promising to alleviate Parkinson’s disease. However, the precise molecular mechanism underlying the coordination of NAMI-A with His and Met residues incompletely elucidated. Herein, the density functional theory (DFT) is used to investigate the binding mechanisms of NAMI-A with two model ligands, N-acetyl-L-methionine (AcMet) and N-acetyl-L-histidine (AcHis). The Gibbs free energies and rate constants indicate that the diaqua hydrolysate of NAMI-A constitutes its pivotal active moiety, wherein the axial water ligand is thermodynamically predisposed to substitution by amino acid residues. Notably, AcMet exhibits a superior binding affinity for Ru(III) in relation to AcHis. Our findings reveal that water ligands are more susceptible to displacement than chloride ligands, underscoring the criticality of the hydrolysis process in the interaction between NAMI-A and biomolecules.