Zn-metalloproteins play vital roles in numerous metabolic processes, making them high-value targets for structure-based drug design. To advance these efforts, it is useful to unravel the individual components of the intermolecular interaction energies (DE) that stabilize the Znbinding cavity, both in the absence and presence of bound protein ligands. Here, we utilize quantum chemistry (QC) to decompose DE into distinct physical contributions. The relative magnitudes of these components vary significantly depending on the coordination number (four to six) and the chemical nature ('hard'vs.'soft') of the Zn-coordinating ligands. These high-level QC analyses serve to calibrate and validate polarizable molecular mechanics potentials, effectively extending the accurate description of electronic effects beyond the immediate Zn-binding cavity to enlarged recognition sites and, ultimately, entire protein systems over long molecular dynamics (MD) simulation timescales. Following a concise overview of our QC methodology, we present validation studies on complexes containing up to 300 atoms and discuss the prospects of applying this framework to large-scale simulations of Zn-metalloprotein-ligand complexes. Finally, the structural and energetic role of discrete, highly polarizable water molecules is highlighted.
Characterizing the solvation of open-shell transition metal ions remains a challenge for classical force fields due to ligand field electronic effects. Here, we present AMOEBA + NN, a machine-learning-augmented polarizable potential, to investigate Cu2+ solvation in NH3 and H2O and mixed environments. The model, trained on quantum-mechanical (QM) association energies, accurately reproduces the Cu2+ energy landscape across diverse coordination geometries. Molecular dynamics simulations demonstrate that AMOEBA + NN successfully captures the electronically driven Jahn–Teller (JT) distortion. Evidence from radial distribution functions (RDFs) and geometry optimizations reveals characteristic axial elongation, which is absent in conventional classical descriptions. Kinetic analysis shows a highly dynamic Cu2+–NH3 environment with a rapid ligand exchange (residence time of 66.52 ps), contrasting with the H2O system where binding is two to three orders of magnitude more stable. Furthermore, the calculated hydration free energy of −477.59 ± 0.50 kcal mol−1 shows excellent agreement with experimental data (within 1.31 kcal mol−1). This work provides a unified, computationally efficient framework for describing the structural, dynamic, and thermodynamic observables of transition metal coordination.
Zhecheng He, Yanxing Wang, Shubham Chatterjee et al.· Chemical Science· 0 citations
