Investigating Polyoxometalate-Protein Interactions at Chemically Distinct Binding Sites

Area of Science:

• Biochemistry
• Computational Chemistry
• Materials Science

Background:

• Human serum albumin (HSA) is a crucial protein for drug transport and has multiple potential cleavage sites.
• Zr-containing Keggin polyoxometalates (ZrK) are investigated for their catalytic and binding properties.

Purpose of the Study:

• To investigate the binding interactions between ZrK and distinct cleavage sites of HSA.
• To elucidate the molecular mechanisms governing ZrK-HSA complexation.
• To evaluate the impact of ZrK binding on HSA's secondary structure and hydrolytic activity.

Main Methods:

• Combined rigid and flexible molecular docking.
• All-atom molecular dynamics simulations.
• Analysis of electrostatic potentials, amino acid residue properties, binding free energies, and secondary structures.
• Isothermal calorimetry experiments.

Main Results:

• ZrK exhibits distinct binding affinities across four identified HSA cleavage sites.
• Binding is primarily mediated by hydrogen bonding (direct and solvent-mediated) and electrostatic interactions.
• Site 4 emerged as the major binding site, with sites 1, 2, and 3 as minor sites, supported by binding free energies (-91.2 kJ/mol for site 4).
• ZrK binding did not significantly alter HSA's overall α-helical secondary structure.
• Hydrolysis of peptide bonds by the substrate maintained its structural integrity.

Conclusions:

• ZrK interacts specifically with HSA, with a preference for site 4.
• The findings provide a detailed molecular understanding of ZrK-protein interactions.
• This research paves the way for designing advanced polyoxometalates with enhanced hydrolytic activities.