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.