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Molecules (Basel, Switzerland) Apr 2022The multiscaling quantum mechanics/molecular mechanics (QM/MM) approach was introduced in 1976, while the extensive acceptance of this methodology started in the 1990s.... (Review)
Review
The multiscaling quantum mechanics/molecular mechanics (QM/MM) approach was introduced in 1976, while the extensive acceptance of this methodology started in the 1990s. The combination of QM/MM approach with molecular dynamics (MD) simulation, otherwise known as the QM/MM/MD approach, is a powerful and promising tool for the investigation of chemical reactions' mechanism of complex molecular systems, drug delivery, properties of molecular devices, organic electronics, etc. In the present review, the main methodologies in the multiscaling approaches, i.e., density functional theory (DFT), semiempirical methodologies (SE), MD simulations, MM, and their new advances are discussed in short. Then, a review on calculations and reactions on metalloproteins is presented, where particular attention is given to nitrogenase that catalyzes the conversion of atmospheric nitrogen molecules N₂ into NH₃ through the process known as nitrogen fixation and the FeMo-cofactor.
Topics: Metalloproteins; Molecular Dynamics Simulation; Nitrogenase; Quantum Theory
PubMed: 35566011
DOI: 10.3390/molecules27092660 -
Methods in Enzymology 2022Carotenoids are a family of pigment compounds, a subset of which are precursors for vitamin A biosynthesis. These pigments are derived from isopentenyl pyrophosphate...
Carotenoids are a family of pigment compounds, a subset of which are precursors for vitamin A biosynthesis. These pigments are derived from isopentenyl pyrophosphate (IPP), with geranylgeranyl diphosphate being the first metabolite unique to carotenoid biosynthesis in plants, algae, fungi, some bacteria, and arthropods. This chapter highlights the metal-dependent enzymes involved in synthesizing carotenoids in plants and the current state of knowledge of their cofactors and mechanisms. Emphasis is given to spectroscopic methods used to characterize metal centers. The recently discovered heme-dependent isomerase Z-ISO is presented as a case study in how to interrogate a metalloenzyme. Use of UV-vis, electron paramagnetic resonance, and magnetic circular dichroism spectroscopies of a metal center at various oxidation states and with external small molecule probes (CN, CO, and NO) can provide information about the nature of the metal center, the identity of its ligands, and its mechanism of action. Z-ISO is a histidine/cysteine ligated heme-dependent enzyme that is only active in the ferrous state and possesses redox-linked ligand switching. The choice and design of experiments are discussed as well as the conclusions that can be drawn.
Topics: Carotenoids; Electron Spin Resonance Spectroscopy; Heme; Metalloproteins; Oxidation-Reduction
PubMed: 35878978
DOI: 10.1016/bs.mie.2022.01.012 -
Biological Trace Element Research Dec 2022Copper (Cu) is a vital microelement required for the optimum growth performance and wellbeing of aquatic animals. It contributed to various biological, physiological,... (Review)
Review
Copper (Cu) is a vital microelement required for the optimum growth performance and wellbeing of aquatic animals. It contributed to various biological, physiological, and metabolic function in the entire body of the aquatic animals. Further, Cu is a cofactor for several enzymes involved in the antioxidation capacity and metalloenzyme formation. Some ingredients used for aquafeed formulation include sufficient amounts of Cu that can provide aquatic animals with their requirements. Nevertheless, in some cases, external Cu sources are needed to optimize the essential needs of aquatic animals. Inorganic, organic, and nano Cu forms are included in aquafeed and result in regulated physiological and biological functions. The addition of Cu should be added at particular doses considering the species, size, duration, and environmental conditions. Water-borne Cu level should also be considered as long as aquatic animals can obtain their requirements through gills to avoid overdosing and toxicity. Several studies reported the optimum doses of Cu required for optimal growth, productivity, and health status in several aquatic animals. This review article presents the up-to-date results of Cu-related studies in aquafeed. It also helps academia design further studies to better understand the border between Cu requirements and toxicity. Besides, planning for more studies involved in the understanding of the primary mode of action of Cu in aquatic animals' entire bodies.
Topics: Animals; Copper; Gills; Metalloproteins; Nutritional Requirements; Water; Water Pollutants, Chemical
PubMed: 35083707
DOI: 10.1007/s12011-021-03079-1 -
Journal of Chemical Information and... Mar 2024Metalloproteins play a fundamental role in molecular biology, contributing to various biological processes. However, the discovery of high-affinity ligands targeting...
Metalloproteins play a fundamental role in molecular biology, contributing to various biological processes. However, the discovery of high-affinity ligands targeting metalloproteins has been delayed due, in part, to a lack of suitable tools and data. Molecular docking, a widely used technique for virtual screening of small-molecule ligand interactions with proteins, often faces challenges when applied to metalloproteins due to the particular nature of the ligand metal bond. To address these limitations associated with docking metalloproteins, we introduce a knowledge-driven docking approach known as "metalloprotein bias docking" (MBD), which extends the AutoDock Bias technique. We assembled a comprehensive data set of metalloprotein-ligand complexes from 15 different metalloprotein families, encompassing Ca, Co, Fe, Mg, Mn, and Zn metal ions. Subsequently, we conducted a performance analysis of our MBD method and compared it to the conventional docking (CD) program AutoDock4, applied to various metalloprotein targets within our data set. Our results demonstrate that MBD outperforms CD, significantly enhancing accuracy, selectivity, and precision in ligand pose prediction. Additionally, we observed a positive correlation between our predicted ligand free energies and the corresponding experimental values. These findings underscore the potential of MBD as a valuable tool for the effective exploration of metalloprotein-ligand interactions.
Topics: Humans; Metalloproteins; Molecular Docking Simulation; Ligands
PubMed: 38373276
DOI: 10.1021/acs.jcim.3c01853 -
Molecules (Basel, Switzerland) Jul 2019Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the... (Review)
Review
Metalloproteins and metalloenzymes play important roles in biological systems by using the limited metal ions, complexes, and clusters that are associated with the protein matrix. The design of artificial metalloproteins and metalloenzymes not only reveals the structure and function relationship of natural proteins, but also enables the synthesis of artificial proteins and enzymes with improved properties and functions. Acknowledging the progress in rational design from single to multiple active sites, this review focuses on recent achievements in the design of artificial metalloproteins and metalloenzymes with metal clusters, including zinc clusters, cadmium clusters, iron-sulfur clusters, and copper-sulfur clusters, as well as noble metal clusters and others. These metal clusters were designed in both native and de novo protein scaffolds for structural roles, electron transfer, or catalysis. Some synthetic metal clusters as functional models of native enzymes are also discussed. These achievements provide valuable insights for deep understanding of the natural proteins and enzymes, and practical clues for the further design of artificial enzymes with functions comparable or even beyond those of natural counterparts.
Topics: Carrier Proteins; Catalysis; Catalytic Domain; Enzymes; Metalloproteins; Metals; Models, Molecular; Molecular Conformation; Molecular Structure; Protein Binding; Protein Engineering
PubMed: 31362341
DOI: 10.3390/molecules24152743 -
Molecules (Basel, Switzerland) Nov 2023The pyranopterin dithiolene ligand is remarkable in terms of its geometric and electronic structure and is uniquely found in mononuclear molybdenum and tungsten enzymes.... (Review)
Review
The pyranopterin dithiolene ligand is remarkable in terms of its geometric and electronic structure and is uniquely found in mononuclear molybdenum and tungsten enzymes. The pyranopterin dithiolene is found coordinated to the metal ion, deeply buried within the protein, and non-covalently attached to the protein via an extensive hydrogen bonding network that is enzyme-specific. However, the function of pyranopterin dithiolene in enzymatic catalysis has been difficult to determine. This focused account aims to provide an overview of what has been learned from the study of pyranopterin dithiolene model complexes of molybdenum and how these results relate to the enzyme systems. This work begins with a summary of what is known about the pyranopterin dithiolene ligand in the enzymes. We then introduce the development of inorganic small molecule complexes that model aspects of a coordinated pyranopterin dithiolene and discuss the results of detailed physical studies of the models by electronic absorption, resonance Raman, X-ray absorption and NMR spectroscopies, cyclic voltammetry, X-ray crystallography, and chemical reactivity.
Topics: Models, Molecular; Molybdenum; Ligands; Metalloproteins; Catalysis; Coenzymes
PubMed: 38005178
DOI: 10.3390/molecules28227456 -
Acta Crystallographica. Section D,... Oct 2021Metalloproteins catalyze a range of reactions, with enhanced chemical functionality due to their metal cofactor. The reaction mechanisms of metalloproteins have been... (Review)
Review
Metalloproteins catalyze a range of reactions, with enhanced chemical functionality due to their metal cofactor. The reaction mechanisms of metalloproteins have been experimentally characterized by spectroscopy, macromolecular crystallography and cryo-electron microscopy. An important caveat in structural studies of metalloproteins remains the artefacts that can be introduced by radiation damage. Photoreduction, radiolysis and ionization deriving from the electromagnetic beam used to probe the structure complicate structural and mechanistic interpretation. Neutron protein diffraction remains the only structural probe that leaves protein samples devoid of radiation damage, even when data are collected at room temperature. Additionally, neutron protein crystallography provides information on the positions of light atoms such as hydrogen and deuterium, allowing the characterization of protonation states and hydrogen-bonding networks. Neutron protein crystallography has further been used in conjunction with experimental and computational techniques to gain insight into the structures and reaction mechanisms of several transition-state metal oxidoreductases with iron, copper and manganese cofactors. Here, the contribution of neutron protein crystallography towards elucidating the reaction mechanism of metalloproteins is reviewed.
Topics: Animals; Catalysis; Crystallography, X-Ray; Humans; Metalloproteins; Models, Molecular; Neutron Diffraction; Neutrons; Oxidoreductases
PubMed: 34605429
DOI: 10.1107/S2059798321009025 -
Chembiochem : a European Journal of... Mar 2024The connection between 3d (Cu) and 4d (Mo) via the "Mo-S-Cu" unit is called Mo-Cu antagonism. Biology offers case studies of such interactions in metalloproteins such as... (Review)
Review
The connection between 3d (Cu) and 4d (Mo) via the "Mo-S-Cu" unit is called Mo-Cu antagonism. Biology offers case studies of such interactions in metalloproteins such as Mo/Cu-CO Dehydrogenases (Mo/Cu-CODH), and Mo/Cu Orange Protein (Mo/Cu-ORP). The CODH significantly maintains the CO level in the atmosphere below the toxic level by converting it to non-toxic CO for respiring organisms. Several models were synthesized to understand the structure-function relationship of these native enzymes. However, this interaction was first observed in ruminants, and they convert molybdate (MoO ) into tetrathiomolybdate (MoS ; TTM), reacting with cellular Cu to yield biological unavailable Mo/S/Cu cluster, then developing Cu-deficiency diseases. These findings inspire the use of TTM as a Cu-sequester drug, especially for treating Cu-dependent human diseases such as Wilson diseases (WD) and cancer. It is well known that a balanced Cu homeostasis is essential for a wide range of biological processes, but negative consequence leads to cell toxicity. Therefore, this review aims to connect the Mo-Cu antagonism in metalloproteins and anti-copper therapy.
Topics: Humans; Copper; Molybdenum; Metalloproteins
PubMed: 38205937
DOI: 10.1002/cbic.202300679 -
Genomics, Proteomics & Bioinformatics Dec 2021Trace elements are required by all organisms, which are key components of many enzymes catalyzing important biological reactions. Many trace element-dependent proteins...
Trace elements are required by all organisms, which are key components of many enzymes catalyzing important biological reactions. Many trace element-dependent proteins have been characterized; however, little is known about their occurrence in microbial communities in diverse environments, especially the global marine ecosystem. Moreover, the relationships between trace element utilization and different types of environmental stressors are unclear. In this study, we used metagenomic data from the Global Ocean Sampling expedition project to identify the biogeographic distribution of genes encoding trace element-dependent proteins (for copper, molybdenum, cobalt, nickel, and selenium) in a variety of marine and non-marine aquatic samples. More than 56,000 metalloprotein and selenoprotein genes corresponding to nearly 100 families were predicted, becoming the largest dataset of marine metalloprotein and selenoprotein genes reported to date. In addition, samples with enriched or depleted metalloprotein/selenoprotein genes were identified, suggesting an active or inactive usage of these micronutrients in various sites. Further analysis of interactions among the elements showed significant correlations between some of them, especially those between nickel and selenium/copper. Finally, investigation of the relationships between environmental conditions and metalloprotein/selenoprotein families revealed that many environmental factors might contribute to the evolution of different metalloprotein and/or selenoprotein genes in the marine microbial world. Our data provide new insights into the utilization and biological roles of these trace elements in extant marine microbes, and might also be helpful for the understanding of how these organisms have adapted to their local environments.
Topics: Copper; Metalloproteins; Microbiota; Nickel; Seawater; Selenium; Selenoproteins; Trace Elements; Water Microbiology
PubMed: 33631428
DOI: 10.1016/j.gpb.2021.02.003 -
International Journal of Molecular... Jul 2019Dimethyl sulfoxide reductases (DMSO) are molybdoenzymes widespread in all domains of life. They catalyse not only redox reactions, but also hydroxylation/hydration and... (Review)
Review
Dimethyl sulfoxide reductases (DMSO) are molybdoenzymes widespread in all domains of life. They catalyse not only redox reactions, but also hydroxylation/hydration and oxygen transfer processes. Although literature on DMSO is abundant, the biological significance of these enzymes in anaerobic respiration and the molecular mechanisms beyond the expression of genes coding for them are still scarce. In this review, a deep revision of the literature reported on DMSO as well as the use of bioinformatics tools and free software has been developed in order to highlight the relevance of DMSO reductases on anaerobic processes connected to different biogeochemical cycles. Special emphasis has been addressed to DMSO from extremophilic organisms and their role in nitrogen cycle. Besides, an updated overview of phylogeny of DMSOs as well as potential applications of some DMSO reductases on bioremediation approaches are also described.
Topics: Coenzymes; Extremophiles; Iron-Sulfur Proteins; Isoenzymes; Metabolic Networks and Pathways; Metalloproteins; Molybdenum; Molybdenum Cofactors; Multigene Family; Nitrogen Cycle; Oxidation-Reduction; Oxidoreductases; Phylogeny; Pteridines; Structure-Activity Relationship; Tungsten
PubMed: 31288391
DOI: 10.3390/ijms20133349