Tetrahedral and Square Planar Ni[(SPR₂)₂N]₂ complexes, R = Ph & ⁱPr Revisited: Experimental and Theoretical Analysis of Interconversion Pathways, Structural Preferences, and Spin Delocalization

Sulfur-containing mono- or bidentate types of ligands, usually form square planar Ni(II)S4 complexes. However, it has already been established that the bidentate L− dithioimidodiphosphinato ligands, [R2P(S)NP(S)R′2]−, R, and R′ = aryl or alkyl, can afford both tetrahedral and square planar, NiS4-containing, homoleptic NiR,R′L2 complexes, owing to an apparent structural flexibility, which has not, so far, been probed. In this work, the literature tetrahedral Ni[R2P(S)NP(S)R2]2 complexes, R = Ph (NiPh,PhL2, 1Td) and R = iPr (NiiPr,iPrL2, 2) as well as the newly synthesized Ni[iPr2P(S)NP(S)Ph2]2 complex (NiiPr,PhL2, 3), have been studied by UV−vis, IR, and 31P NMR spectroscopy. Complex 3 was shown by X-ray crystallography to be square planar, and magnetic studies confirmed that it is diamagnetic in the solid state. However, it becomes paramagnetic in solution, as it shows a similar UV−vis spectrum to one of the tetrahedral 1Td and 2 complexes. The crystal structure of the potassium salt of the asymmetric ligand, [iPr2P(S)NP(S)Ph2]K, has also been determined and compared to those of the protonated iPr2P(S)NHP(S)Ph2 ligand and complex 3. All three, 1Td, 2, and 3, NiR,R′L2 complexes show strong paramagnetic effects in their solution 31P NMR spectra. The magnetic properties of paramagnetic complexes 1 and 2 in the solid state were investigated on oriented crystals, and their analysis afforded remarkably small values of the spin−orbit coupling constant (λ) and orbital reduction factor (k) parameters, implying significant delocalization of unpaired electronic density toward the ligands. The above experimental findings are combined with data from standard density functional theory and correlated multiconfiguration ab initio theoretical methods, in an effort to investigate the interplay between the square planar and tetrahedral geometries of the NiS4 core, the mechanistic pathway for the spin-state interconversion, the degree of covalency of the Ni−S bonds, and the distribution of the spin density in this type of system. The analysis provides justification for the structural flexibility of such ligands, affording NiR,R′L2 complexes with variable metallacycle conformation and NiS4 core geometries. Of particular importance are the large zero-field splitting values estimated by both experimental and theoretical means, which have not, as yet, been verified by direct methods, such as electron paramagnetic resonance spectroscopy. The findings of our work confirm earlier observations on the feasibility of synthesizing either tetrahedral or square planar NiS4 complexes containing the same type of ligands. They can also form the basis of investigating structure−properties relationships in other NiS4-containing systems

High-frequency EPR study of the high-spin FeII complex Fe[(SPPh2)2N]2

We report continuous-wave electron-paramagnetic-resonance (EPR) spectra of the high-spin FeII complex Fe[(SPPh2)2N] 2 at 275.7 GHz, 94.1 GHz and 9.5 GHz. Combined analysis of these EPR spectra shows that the complex occurs in multiple conformations. For two main conformations the spin-Hamiltonian parameters, which reflect the electronic structure of the complex, are accurately determined: (1) D=9.17cm-1 (275 GHz), E/D=0.021 and (2) D=8.87cm-1 (266 GHz), E/D=0.052. The EPR spectra obtained at 275.7 GHz on single crystals of the complex are essential for the analysis and in addition they reveal that the two main conformations occur at two magnetically distinguishable sites. © 2012 Elsevier Inc. All rights reserved

Superhelical architecture of the myosin filament-linking protein myomesin with unusual elastic properties

Active muscles generate substantial mechanical forces by the contraction/relaxation cycle, and, to maintain an ordered state, they require molecular structures of extraordinary stability. These forces are sensed and buffered by unusually long and elastic filament proteins with highly repetitive domain arrays. Members of the myomesin protein family function as molecular bridges that connect major filament systems in the central M-band of muscle sarcomeres, which is a central locus of passive stress sensing. To unravel the mechanism of molecular elasticity in such filament-connecting proteins, we have determined the overall architecture of the complete C-terminal immunoglobulin domain array of myomesin by X-ray crystallography, electron microscopy, solution X-ray scattering, and atomic force microscopy. Our data reveal a dimeric tail-to-tail filament structure of about 360 Å in length, which is folded into an irregular superhelical coil arrangement of almost identical α-helix/domain modules. The myomesin filament can be stretched to about 2.5-fold its original length by reversible unfolding of these linkers, a mechanism that to our knowledge has not been observed previously. Our data explain how myomesin could act as a highly elastic ribbon to maintain the overall structural organization of the sarcomeric M-band. In general terms, our data demonstrate how repetitive domain modules such as those found in myomesin could generate highly elastic protein structures in highly organized cell systems such as muscle sarcomeres

Is Exposure to BMAA a Risk Factor for Neurodegenerative Diseases? : A Response to a Critical Review of the BMAA Hypothesis

In a literature survey, Chernoff et al. (2017) dismissed the hypothesis that chronic exposure to beta-N-methylamino-L-alanine (BMAA) may be a risk factor for progressive neurodegenerative disease. They question the growing scientific literature that suggests the following: (1) BMAA exposure causes ALS/PDC among the indigenous Chamorro people of Guam; (2) Guamanian ALS/PDC shares clinical and neuropathological features with Alzheimer's disease, Parkinson's disease, and ALS; (3) one possible mechanism for protein misfolds is misincorporation of BMAA into proteins as a substitute for L-serine; and (4) chronic exposure to BMAA through diet or environmental exposures to cyanobacterial blooms can cause neurodegenerative disease. We here identify multiple errors in their critique including the following: (1) their review selectively cites the published literature; (2) the authors reported favorably on HILIC methods of BMAA detection while the literature shows significant matrix effects and peak coelution in HILIC that may prevent detection and quantification of BMAA in cyanobacteria; (3) the authors build alternative arguments to the BMAA hypothesis, rather than explain the published literature which, to date, has been unable to refute the BMAA hypothesis; and (4) the authors erroneously attribute methods to incorrect studies, indicative of a failure to carefully consider all relevant publications. The lack of attention to BMAA research begins with the review's title which incorrectly refers to BMAA as a "non-essential" amino acid. Research regarding chronic exposure to BMAA as a cause of human neurodegenerative diseases is emerging and requires additional resources, validation, and research. Here, we propose strategies for improvement in the execution and reporting of analytical methods and the need for additional and well-executed inter-lab comparisons for BMAA quantitation. We emphasize the need for optimization and validation of analytical methods to ensure that they are fit-for-purpose. Although there remain gaps in the literature, an increasingly large body of data from multiple independent labs using orthogonal methods provides increasing evidence that chronic exposure to BMAA may be a risk factor for neurological illness

Role of κ→λ light-chain constant-domain switch in the structure and functionality of A17 reactibody

The engineering of catalytic function in antibodies requires precise information on their structure. Here, results are presented that show how the antibody domain structure affects its functionality. The previously designed organophosphate-metabolizing reactibody A17 has been re-engineered by replacing its constant κ light chain by the λ chain (A17λ), and the X-ray structure of A17λ has been determined at 1.95 Å resolution. It was found that compared with A17κ the active centre of A17λ is displaced, stabilized and made more rigid owing to interdomain interactions involving the CDR loops from the VL and VH domains. These VL/VH domains also have lower mobility, as deduced from the atomic displacement parameters of the crystal structure. The antibody elbow angle is decreased to 126° compared with 138° in A17κ. These structural differences account for the subtle changes in catalytic efficiency and thermodynamic parameters determined with two organophosphate ligands, as well as in the affinity for peptide substrates selected from a combinatorial cyclic peptide library, between the A17κ and A17λ variants. The data presented will be of interest and relevance to researchers dealing with the design of antibodies with tailor-made functions

Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers

Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors