title: Modeling Zn²⁺ release from metallothionein.
abstract: Mammalian metallothioneins (MTs) comprise a Zn3Cys9 cluster in the β domain and a Zn4Cys11 cluster in the α domain. They play a crucial role in storing and donating Zn(2+) ions to target metalloproteins and have been implicated in several diseases, thus understanding how MTs release Zn(2+) is of widespread interest. In this work, we present a strategy to compute the free energy for releasing Zn(2+) from MTs using a combination of classical molecular dynamics (MD) simulations, quantum-mechanics/molecular-mechanics (QM/MM) minimizations, and continuum dielectric calculations. The methodology is shown to reproduce the experimental observations that (1) the Zn-binding sites do not have equal Zn(2+) affinity and (2) the isolated β domain is thermodynamically less stable and releases Zn(2+) faster with oxidizing agents than the isolated α domain. It was used to compute the free energies for Zn(2+) release from the metal cluster in the absence and presence of the protein matrix (protein architecture and coupled protein-water interactions) to yield the respective disulfide-bonded product. The results show the importance of the protein matrix as well as protein dynamics and coupled conformational changes in accounting for the differential Zn(2+)-releasing propensity of the two domains with oxidizing agents.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica , Taipei 115, Taiwan , R.O.C.
authors.forename: C Satheesan
authors.initials: CS
authors.lastname: Babu
authors.forename: Yu-Ming
authors.initials: YM
authors.lastname: Lee
authors.forename: Todor
authors.initials: T
authors.lastname: Dudev
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D002138:Calibration; D002413:Cations, Divalent / Q000737:chemistry; D006801:Humans; D008668:Metallothionein / Q000737:chemistry*; D008958:Models, Molecular; D016877:Oxidants / Q000737:chemistry; D011487:Protein Conformation; D011789:Quantum Theory; D013816:Thermodynamics; D014867:Water / Q000737:chemistry; D015032:Zinc / Q000737:chemistry*
chemical_list: D002413:Cations, Divalent; D016877:Oxidants; D014867:Water; D008668:Metallothionein; D015032:Zinc