Assessment of Molecular Mechanics-based Zn2+ Models in Mono- and Bimetallic Ligand Binding Sites

Zn 2+ ions play an important role in biology, but accurate sampling of metalloproteins using Molecular Mechanics remains challenging. Several models have been proposed to describe Zn 2+ in biomolecular simulations, ranging from nonbonded models, employing classical 12-6 Lennard-Jones (LJ) potentials or extended LJ-potentials, to dummy-atom models and bonded models. We evaluated the performance of a large variety of these Zn 2+ models in two challenging environments for which little is known about the performance of these methods, namely in a monometallic (Carbonic Anhydrase II) and a bimetallic ligand binding site (metallo-β-lactamase VIM-2). We focused on properties which are important for a stable, correct binding site description during molecular dynamics (MD) simulations, because a proper treatment of the metal coordination and forces are here essential. We observed that the strongest difference in performance of these Zn 2+ models can be found in the description of interactions between Zn 2+ and non-charged ligating atoms, such as the imidazole nitrogen in histidine residues. We further show that the nonbonded (12-6 LJ) models struggle most in the description of Zn 2+ -biomolecule interactions, while the inclusion of ion-induced dipole effects strongly improves the description between Zn 2+ and non-charged ligating atoms. The octahedral dummy-atom models result in highly stable simulations and correct Zn 2+ coordination, and are therefore highly suitable for binding sites containing an octahedral coordinated Zn 2+ ion. The results from this evaluation study in ligand binding sites can guide structural studies of Zn 2+ containing proteins, such as MD-refinement of docked ligand poses and long-term MD simulations.