Benchmarking biomolecular force field-based Zn 2+ for mono- and bimetallic ligand binding sites.

Zn 2+ is one of the most versatile biologically available metal ions, but accurate modeling of Zn 2+ -containing metalloproteins at the biomolecular force field level can be challenging. Since most Zn 2+ models are parameterized in bulk solvent, in-depth knowledge about their performance in a protein environment is limited. Thus, we systematically investigate here the behavior of non-polarizable Zn 2+ models for their ability to reproduce experimentally determined metal coordination and ligand binding in metalloproteins. The benchmarking is performed in challenging environments, including mono- (carbonic anhydrase II) and bimetallic (metallo-β-lactamase VIM-2) ligand binding sites. We identify key differences in the performance between the Zn 2+ models with regard to the preferred ligating atoms (charged/non-charged), attraction of water molecules, and the preferred coordination geometry. Based on these results, we suggest suitable simulation conditions for varying Zn 2+ site geometries that could guide the further development of biomolecular Zn 2+ models.