Modeling Zn²⁺ release from metallothionein.

Area of Science:

• Biochemistry
• Computational Biology
• Biophysics

Background:

• Mammalian metallothioneins (MTs) are crucial for zinc (Zn2+) homeostasis, storing and donating Zn2+ to metalloproteins.
• MTs are implicated in various diseases, making their Zn2+ release mechanisms a significant research area.

Purpose of the Study:

• To develop and validate a computational strategy for calculating the free energy of Zn2+ release from MTs.
• To investigate the differential Zn2+ release propensities of MT domains and the role of the protein matrix.

Main Methods:

• Combined classical molecular dynamics (MD) simulations, quantum-mechanics/molecular-mechanics (QM/MM) minimizations, and continuum dielectric calculations.
• Calculated free energies for Zn2+ release from MTs in the presence and absence of the protein matrix.

Main Results:

• The computational method accurately reproduced experimental findings on differential Zn2+ binding affinities and domain-specific release rates.
• The study quantified the free energies of Zn2+ release, highlighting the influence of the protein matrix, dynamics, and conformational changes.
• The β domain showed lower thermodynamic stability and faster Zn2+ release with oxidizing agents compared to the α domain.

Conclusions:

• The protein matrix, protein dynamics, and coupled conformational changes are critical factors influencing the differential Zn2+ release from MT domains.
• The developed computational approach provides a valuable tool for studying Zn2+ dynamics in MTs and related biological processes.