Characterization of the dizinc analogue of the synthetic diiron protein DF1 using ab initio and hybrid quantum/classical molecular dynamics simulations

The structural and dynamical properties of the four alpha-helix bundle Due Ferri 1, which is a generic mimic of diiron proteins, have been explored using density functional theory (DFT) based and hybrid quantum/classical molecular dynamics (QM/MM) simulations. Four quantum mechanical (QM) representations of the active site have been employed in order to systematically assess the role of first and second shell interactions: (a) a 66-atom fragment of the active site comprising only first shell ligands, (b and c) two systems (78 and 86 atoms) containing different second shell hydrogen bonds, and (d) a 98-atom model including both the first and second shell residues. Two QM/MM partitioning schemes have been explored in order to explicitly consider the role of the whole protein environment: (a) a 54-QM-atom model in which only the first shell ligands are described at the DFT level, while the rest of the protein environment is taken into account at the MM level and (b) a 68-QM-atom model in which the first shell ligands plus a second shell hydrogen bond network is considered at the DFT level. All of the calculations confirm the highly flexible nature of the carboxylate-bridged binuclear motif and demonstrate the importance of the whole protein environment in stabilizing the hydrogen bond networks that surround the active site. The present QM/MM approach allows for the identification of key factors governing the stability/reactivity of the active site and thus provides unique insights that can be exploited for the future tailoring of new highly selective biomimetic enzymatic compounds.