Benchmarking biomolecular force field-based Zn2+ for mono- and bimetallic ligand binding sites

Zn2+ is one of the most versatile biologically available metal ions, but accurate modeling of Zn2+-containing metalloproteins at the biomolecular force field level can be challenging. Since most Zn2+ 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 Zn2+ 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-beta-lactamase VIM-2) ligand binding sites. We identify key differences in the performance between the Zn2+ 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 Zn2+ site geometries that could guide the further development of biomolecular Zn2+ models.

Automated summary

We systematically investigate the behavior of non-polarizable Zn2+ models in reproducing experimentally determined metal coordination and ligand binding in metalloproteins. Key differences in the performance of these models are identified, including the preferred ligating atoms, attraction of water molecules, and coordination geometry preferences. Suitable simulation conditions for different Zn2+ site geometries are suggested based on the results.