Principles Governing Mg, Ca, and Zn Binding and Selectivity in Proteins

The role of the second shell in the process of metal binding and selectivity in metalloproteins has been elucidated by combining Protein Data Bank (PDB) surveys of Mg, Mn, Ca, and Zn binding sites with density functional theory/continuum dielectric methods (DFT/CDM). Peptide backbone groups were found to be the most common second-shell ligand in Mg, Mn, Ca, and Zn binding sites, followed (in decreasing order) by Asp/Glu, Lys/Arg, Asn/Gln, and Ser/Thr side chains. Aromatic oxygen- or nitrogen-containing side chains (Tyr, His, and Trp) and sulfur-containing side chains (Cys and Met) are seldom found in the second coordination layer. The backbone and Asn/Gln side chain are ubiquitous in the metal second coordination layer as their carbonyl oxygen and amide hydrogen can act as a hydrogen-bond acceptor and donor, respectively, and can therefore partner practically every first-shell ligand. The second most common outer-shell ligand, Asp/Glu, predominantly hydrogen bonds to a metal-bound water or Zn-bound histidine and polarizes the H-O or H-N bond. In certain cases, a second-shell Asp/Glu could affect the protonation state of the metal ligand. It could also energetically stabilize a positively charged metal complex more than a neutral ligand such as the backbone and Asn/Gln side chain. As for the first shell, the second shell is predicted to contribute to the metal selectivity of the binding site by discriminating between metal cations of different ionic radii and coordination geometries. The first-shell-second-shell interaction energies decay rapidly with increasing solvent exposure of the metal binding site. They are less favorable but are of the same order of magnitude as compared to the respective metal-first-shell interaction energies. Altogether, the results indicate that the structure and properties of the second shell are dictated by those of the first layer. The outer shell is apparently designed to stabilize/protect the inner-shell and complement/enhance its properties.

First−Second Shell Interactions in Metal Binding Sites in Proteins: A PDB Survey and DFT/CDM Calculations

The detailed mechanism of metal−cysteine binding is still poorly understood. It is not clear if every metal cation can induce cysteine deprotonation, how the dielectric medium affects this process,...

Factors governing the protonation state of cysteines in proteins: an Ab initio/CDM study.

New developments in applying quantum mechanics to proteins

Before computational results can be reliably interpreted, it is critical to calibrate the theoretical calculations with respect to appropriate experimental data. Such calibrations have been carried out for biologically important zinc−cysteinate complexes in this work. Calculations using different quantum mechanical methods were carried out to determine the theory/basis set that can reproduce the X-ray structure of a zinc−cysteinate-like complex and the measured gas-phase deprotonation free energy of H2S. The S-VWN/6-311++G(d,p) method was found to reproduce the X-ray geometry of bis-(ethane-1,2-dithiolato-S,S‘)-zinc(II). In particular, it yielded an average Zn−S bond distance of 2.34 A for bis-(ethane-1,2-dithiolato-S,S‘)-zinc(II) and [Zn(CH3S-)4]2-, in excellent agreement with experiment. In contrast, B3-LYP with the same basis set overestimated the average Zn−S bond distance by about 0.1 A. With the 6-311++G(d,p) basis set, MP2 and post-MP2 methods could reproduce the experimental gas-phase deprotonatio...

Modeling Zn2+-Cysteinate Complexes in Proteins

By using quantum chemistry methods, including ab initio Hartree−Fock (HF), as well as the Density Functional Theory approach employing B3LYP approximation, the reaction profiles of three cyclic disulfide species with model zinc finger domains in the HIV-1 nucleocapsid protein (NCp7) have been analyzed. It is shown that the disulfide molecules can act as efficient agents destroying the tetrahedral coordination sphere of the zinc finger domains. The consequence of the reaction is a break of one of the Zn−S bonds and removal of the corresponding molecular thiolate group from the domain by forming a new S−S bond between sulfur atoms from the withdrawing fragment and of the electrophilic agent. As a result of this process the zinc-containing site transforms from the initial tetrahedral geometry to a planar geometry configuration. This transformation further facilitates destruction of the metal binding site. The calculations explicitly show correlations between redox potentials of the electrophilic agents, thei...

Ming Chao

Papers

Quantum Chemical Studies of Reactions of the Cyclic Disulfides with the Zinc Finger Domains in the HIV-1 Nucleocapsid Protein (NCp7)