Reaction of Cysteine and Selenocysteine with a Model Au(I)-N-Heterocyclic Carbene Complex: A QM and QM/MM MD Comparative Study

The substitution reaction of a model Au(I)-N-heterocyclic carbene (NHC) complex with cysteine and selenocysteine represents a key elementary step in the inhibition mechanism of thioredoxin reductase by gold-based metallodrugs. We present a systematic quantum-mechanical (QM) and combined QM/MM investigation of this reaction with the aim of assessing the consistency and reliability of activation and reaction free energies obtained at different theoretical levels. The reaction was first studied at the QM level using several density functional theory (DFT) functionals and basis sets and subsequently within a QM/MM framework, employing multiple QM descriptions of the reactive region and explicit molecular-mechanics (MM) treatment of the solvent (water). Comparison of QM and QM/MM results reveals how the inclusion of the surrounding environment affects both activation barriers and reaction energies. Several protonation states of cysteine and selenocysteine were considered, and a pH-dependent model was constructed using a grand-canonical transformation of the free energy. Combining QM/MM reaction energetics with pKa values yielded pH-dependent Gibbs–Alberty free energy profiles with a coordination-preference switch at pH ≈ 8. In acidic and neutral solutions the Au(I) complex coordinates with selenocysteine, while in a basic environment, coordination with cysteine is energetically more stable.