Structural characterization of [VO(salicylhydroximate)(CH3OH)]3: Applications to the biological chemistry of vanadium(V)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28085/1/0000531.pd

How Outer Coordination Sphere Modifications Can Impact Metal Structures in Proteins: A Crystallographic Evaluation

A challenging objective of de novo metalloprotein design is to control of the outer coordination spheres of an active site to fine tune metal properties. The well‐defined three stranded coiled coils, TRI and CoilSer peptides, are used to address this question. Substitution of Cys for Leu yields a thiophilic site within the core. Metals such as HgII, PbII, and AsIII result in trigonal planar or trigonal pyramidal geometries; however, spectroscopic studies have shown that CdII forms three‐, four‐ or five‐coordinate CdIIS3(OH2)x (in which x=0–2) when the outer coordination spheres are perturbed. Unfortunately, there has been little crystallographic examination of these proteins to explain the observations. Here, the high‐resolution X‐ray structures of apo‐ and mercurated proteins are compared to explain the modifications that lead to metal coordination number and geometry variation. It reveals that Ala substitution for Leu opens a cavity above the Cys site allowing for water excess, facilitating CdIIS3(OH2). Replacement of Cys by Pen restricts thiol rotation, causing a shift in the metal‐binding plane, which displaces water, forming CdIIS3. Residue d‐Leu, above the Cys site, reorients the side chain towards the Cys layer, diminishing the space for water accommodation yielding CdIIS3, whereas d‐Leu below opens more space, allowing for equal CdIIS3(OH2) and CdIIS3(OH2)2. These studies provide insights into how to control desired metal geometries in metalloproteins by using coded and non‐coded amino acids.Controlling coordination geometries: The high‐resolution X‐ray structures of apo‐ and mercurated proteins were compared to explain the modifications that lead to metal coordination number and geometry variation. These studies provide insights into how to control desired metal geometries in metalloproteins by using coded and noncoded amino acids.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149308/1/chem201806040-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149308/2/chem201806040.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149308/3/chem201806040_am.pd

Pathway of formation and catalase activity in a dioxo bridged Mn(IV) dimer.

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29204/1/0000258.pd

Low valent, dinuclear manganese complexes as functional models for manganese catalases

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The Importance of Stereochemically Active Lone Pairs For Influencing Pb II and As III Protein Binding

The toxicity of heavy metals, which is associated with the high affinity of the metals for thiolate rich proteins, constitutes a problem worldwide. However, despite this tremendous toxicity concern, the binding mode of As III and Pb II to proteins is poorly understood. To clarify the requirements for toxic metal binding to metalloregulatory sensor proteins such as As III in ArsR/ArsD and Pb II in PbrR or replacing Zn II in δ‐aminolevulinc acid dehydratase (ALAD), we have employed computational and experimental methods examining the binding of these heavy metals to designed peptide models. The computational results show that the mode of coordination of As III and Pb II is greatly influenced by the steric bulk within the second coordination environment of the metal. The proposed basis of this selectivity is the large size of the ion and, most important, the influence of the stereochemically active lone pair in hemidirected complexes of the metal ion as being crucial. The experimental data show that switching a bulky leucine layer above the metal binding site by a smaller alanine residue enhances the Pb II  binding affinity by a factor of five, thus supporting experimentally the hypothesis of lone pair steric hindrance. These complementary approaches demonstrate the potential importance of a stereochemically active lone pair as a metal recognition mode in proteins and, specifically, how the second coordination sphere environment affects the affinity and selectivity of protein targets by certain toxic ions. Experimental and computational methods have been employed to study the influence of the lone pair of As III and Pb II for the binding of these ions in proteins using designed peptide models. The results show that the mode of coordination of As III and Pb II is greatly influenced by the steric bulk within the second coordination environment of the metals (see figure).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90414/1/chem_201102786_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/90414/2/2040_ftp.pd

The synthesis and reactivity of peroxovanadium complexes as models for vanadium haloperoxidase.

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Mechanistic Analysis of Nucleophilic Substrates Oxidation by Functional Models of Vanadium-Dependent Haloperoxidases: A Density Functional Theory Study

Density functional theory has been used to investigate the structural, electronic, and reactivity properties of an established functional model for vanadium-dependent haloperoxidases, K[VO(O 2 )Hheida] (Hheida 2– = 2,2′-[(2-hydroxyethyl)imino]diacetate). Possible solution species were determined on the basis of potential exogenous donors present under the conditions necessary for reactivity. The energetically favored solution-state species is a 1:1 complex of Hheida and vanadium with a coordinated hydroxyethyl donor trans to the vanadium–oxido bond which is in agreement with the reported solid-state structure for K[VO(O 2 )Hheida]. Transition states of the oxidation reaction were located for four substrates: chloride, bromide, iodide, and dimethyl sulfide. The role of protonation and its effects on reactivity were examined for each substrate. Protonation of the peroxido moiety leads to a significant drop in the activation barrier for oxidation. In contrast no transition states could be located for an oxido-transfer process involving the oxido ligand. Barriers of activation calculated for halide oxidation were similar, providing support to the hypothesis that the p K a of the halide in acetonitrile is responsible for the decrease in reactivity between I – , Br – , and Cl – . The results presented herein provide a mechanistic correlation between a functional model and the enzyme, making K[VO(O 2 )Hheida] a “complete” functional model for vanadium-dependent haloperoxidase.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55972/1/515_ftp.pd

Assessing Guest Selectivity within Metallacrown Host Compartments

15-MC-5 complexes associate in the solid state to form chiral compartments capable of binding guests. Using small molecular yardsticks, we are able to assess the size restrictions of these structures. Dicarboxylate guests that are too short to span the Gd III ions are stabilized by solvates that hydrogen bond to the uncoordinated carboxylate, while guests that are too long destroy the weakly associated structure. We also demonstrate that all that is required for guest encapsulation is unsaturation of the chain connection carboxylates rather than necessitating the presence of aromaticity. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56027/1/1347_ftp.pd

The effect of protonation on [Mn(IV)(μ 2 -O)] 2 complexes

The series of complexes [Mn(IV)(X-SALPN)(μ 2 -O)] 2 , 1 : X=5-OCH 3 ; 2 : X=H; 3 : X=5-Cl; 4 : X=3,5-diCl; 5 : X=5-NO 2 , contain [Mn 2 O 2 ] 4+ cores with Mn-Mn separations of 2.7 Å. These molecules can be protonated to form [Mn(IV)(X-SALPN)(μ 2 -O,OH)] 2 + in which a bridging oxide is protonated. The pK a values for the series of [Mn(IV)(X-SALPN)(μ 2 -O,OH)] 2 + track linearly versus the shift in redox potential with a slope of 84 mV/pKa. This observation suggests that the [Mn 2 O 2 ] 4+ core can be considered as a unit in which the free energy of protonation is directly related to the ability to reduce the Mn(IV) ion. The marked sensitivity of the reduction potential to the presence of protons presents a mechanism in which an enzyme can control the oxidizing capacity of an oxo manganese cluster by the degree and timing of oxo bridge protonation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43535/1/11120_2004_Article_BF00046754.pd