10.1021/ct200812y.s001 Jiajing Zhang Jiajing Zhang Wei Yang Wei Yang Jean-Philip Piquemal Jean-Philip Piquemal Pengyu Ren Pengyu Ren Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential American Chemical Society 2012 modeling Structural Coordination protein side chains binding coordination matrix polarization effect metalloproteinase Zn inhibitor MMP 2012-04-10 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Modeling_Structural_Coordination_and_Ligand_Binding_in_Zinc_Proteins_with_a_Polarizable_Potential/2532340 As the second most abundant cation in the human body, zinc is vital for the structures and functions of many proteins. Zinc-containing matrix metalloproteinases (MMPs) have been widely investigated as potential drug targets in a range of diseases ranging from cardiovascular disorders to cancers. However, it remains a challenge in theoretical studies to treat zinc in proteins with classical mechanics. In this study, we examined Zn<sup>2+</sup> coordination with organic compounds and protein side chains using a polarizable atomic multipole-based electrostatic model. We find that the polarization effect plays a determining role in Zn<sup>2+</sup> coordination geometry in both matrix metalloproteinase (MMP) complexes and zinc-finger proteins. In addition, the relative binding free energies of selected inhibitors binding with MMP13 have been estimated and compared with experimental results. While not directly interacting with the small molecule inhibitors, the permanent and polarizing field of Zn<sup>2+</sup> exerts a strong influence on the relative affinities of the ligands. The simulation results also reveal that the polarization effect on binding is ligand-dependent and thus difficult to incorporate into fixed-charge models implicitly.