Modeling Structural Coordination and Ligand Binding in Zinc Proteins with a Polarizable Potential

Area of Science:

• Computational Chemistry
• Biochemistry
• Structural Biology

Background:

• Zinc is the second most abundant cation in the human body, essential for protein structure and function.
• Zinc-containing matrix metalloproteinases (MMPs) are crucial drug targets for diseases including cancer and cardiovascular disorders.
• Accurately modeling zinc ions in proteins using classical mechanics remains a significant theoretical challenge.

Purpose of the Study:

• To investigate the coordination of Zn(2+) with organic compounds and protein side chains.
• To evaluate the impact of polarization effects on Zn(2+) coordination geometry in metalloproteinases and zinc-finger proteins.
• To estimate and compare the binding free energies of MMP13 inhibitors with experimental data.

Main Methods:

• Utilized a polarizable atomic multipole-based electrostatic model to examine Zn(2+) coordination.
• Simulated Zn(2+) interactions with organic molecules and amino acid residues.
• Estimated relative binding free energies for MMP13 inhibitors and compared them with experimental findings.

Main Results:

• Polarization effects significantly determine Zn(2+) coordination geometry in both MMP complexes and zinc-finger proteins.
• The Zn(2+) ion's electrostatic field, including polarization, strongly influences ligand binding affinities to MMP13, even without direct interaction.
• The polarization effect on binding is ligand-dependent, posing challenges for implicit fixed-charge models.

Conclusions:

• Accurate modeling of zinc ion polarization is essential for understanding its role in protein function and drug design.
• The study provides insights into the complex interactions governing ligand binding to metalloproteinases.
• Findings underscore the limitations of fixed-charge models in representing zinc-ligand interactions and suggest the need for polarizable models in drug discovery targeting zinc-dependent proteins.