金属离子对金属蛋白结构与功能的调控

生命金属在生命过程中以不同的化学方式发挥着重要的作用。质膜、细胞器膜等使不同的生命金属在生物体系中有着不同的隔室化分布,相应的金属蛋白或金属伴侣蛋白在维持金属离子内稳态(homeostasis)中起着关键作用。生命体系中广泛存在着具有两个以上金属离子结合部位的金属蛋白。在确定的生理微环境下,由于金属离子结合热力学性质的不等价,该类金属蛋白的生物学功能取决于所结合金属离子的种类及多少。本文以伴刀豆球蛋白A、铜/锌超氧化物歧化酶、中心蛋白、锌指蛋白为例,介绍了金属离子在调控金属蛋白生物学功能中的作用。因此,深入研究金属离子与金属蛋白结合的热力学性质对于理解生命过程的无机化学基础具有重要意义。     

计算机辅助的金属蛋白设计与改造研究进展

金属蛋白是一类含有金属离子的蛋白的统称,具有特殊的催化活性,在生物体中发挥着重要作用,其结构与功能的关系已经得到了较为充分的研究。在此基础上,通过模拟已知金属蛋白的活性位点,利用计算机辅助设计的方法可以人工设计得到具有特定结构和功能的金属蛋白。本文综述了近期计算机辅助金属蛋白设计与改造领域的研究进展,概括了引入金属离子结合位点和改造蛋白活性的一般规律,总结了计算机辅助设计的优势以及目前存在的问题和挑战,并展望了此领域未来发展的方向和可能的突破点。     

新四胺大环配体铜（Ⅱ）,锌（Ⅱ）配合物的结构

新四胺大环配体铜（Ⅱ）、锌（Ⅱ）配合物的结构卜显和曹希传袁满雪安道利陈荣悌（南开大学化学系天津３０００７１近年来，带有功能性侧臂的大环配体与金属离子的配位化学性质的研究受到广泛的关注，因为对这些体系的研究能更好地理解某些金属酶和金属蛋白中的金属离子的...     

我国生物无机化学的发展

叙述了生物无机在我国的发展。着重从金属离子及其配合物与生物大分子的作用、药物中的金属及抗癌活性配合物的作用机理、稀土元素生物无机化学、金属离子与细胞的作用、金属蛋白与金属酶、生物矿化、环境生物无机化学等七个方面综述了我国已取得的进展和成绩。     

金属离子对蛋白质的折叠、识别、自组装及功能的影响*

金属离子不仅影响金属蛋白的空间结构,还与生物大分子的识别、自组装等性质和生物功能密切相关。在很多蛋白质中,金属离子及其配合物可以诱导周围的肽段折叠成正确的结构,我们将其称为金属结合部位作为模板诱导的结构基序（Template-mediated structural motif,TMSM)。深入研究金属离子在蛋白质-核酸自组装体系中生物大分子交联及聚集体中的作用,对理解生命的无机化学基础具有重要意义。     

Cu（Ⅱ）-四氮杂十四环-NCS配合物的合成及其晶体结构

希夫碱以及希夫碱与金属离子的配合物具有较好的杀菌、抗癌和某些催化作用[1-3].在金属蛋白模型、磁性相互作用、分子识别,主客体化学以及电致发光、电子传送材料 [4-7]等方面有着十分重要的应用.     

金属-血清白蛋白的结构研究(Ⅴ)——钴离子与HSA和BSA的相互作用

血清白蛋白是血清中含量最丰富的蛋白质,是多种金属离子的输运蛋白。钴(Ⅱ)离子在金属蛋白研究中经常被用作光谱探针。但Co(Ⅱ)与血清白蛋白的相互作用却很少被研究。     

蛋白质功能的扩展与人工金属结合位点的理性设计

生物体系中金属离子在调节金属蛋白的结构和功能中发挥着至关重要的作用。本文综述了利用人工金属结合位点的理性设计来扩展蛋白质功能范围的研究进展,包括在蛋白分子内部通过探索潜在的结合金属位点、重新设计已有的金属结合位点、以及设计全新的金属结合位点的方法来设计人工金属结合位点,和在蛋白分子表面进行设计,来获得结构及功能的转化、研究与纳米材料间的相互作用、以及进行蛋白质分子的自组装。这些研究进展极大地丰富了我们对金属蛋白结构与功能关系的认识。同时,也赋予了我们控制及利用感兴趣蛋白的能力。     

确定金属酶及模拟络合物中金属离子氧化态的一种方法——键价和分析

在生物化学领域中弄清金属酶活性中心的结构和氧化态是至关重要的。“键价和分析”是根据金属 配体键长数据确定固体中金属离子氧化态的一种方便可行的方法 ,它已用于金属蛋白、金属酶以及高温超导体中金属氧化态的指派。本文拟介绍该方法的要点及其实际应用。     

血红素蛋白的分子设计新趋向

综述了近年来有关血红素蛋白分子设计所出现的新趋向， 包括氨基酸选择突变与血红素修饰相结合，非天然辅基的引入，非天然氨基酸的引入，辅基与蛋白肽链的共价结合，以及全新血红素蛋白的设计与构建5个方面。这些新发展趋向对研究金属蛋白的结构-功能关系提供了重要的信息，同时也为这些理性设计的新颖金属蛋白分子拓宽了其在生物化学、生物工程和药学上的应用。     

De novo design of a redox-active minimal rubredoxin mimic

Metal-binding sites in metalloproteins frequently occur at the interfaces of elements of secondary structure, which has enabled the retrostructural analysis of natural proteins and the de novo design of helical bundles that bind metal ion cofactors. However, the design of metalloproteins containing beta-structure is less well developed, despite the frequent occurrence of beta-conformations in natural metalloproteins. Here, we describe the design and construction of a beta-protein, RM1, that forms a stable, redox-active 4-Cys thiolate Fe(II/III) site analogous to the active site of rubredoxin. The protein folds into a beta-structure in the presence and absence of metal ions and binds Fe(II/III) to form a redox-active site that is stable to repeated cycles of oxidation and reduction, even in an aerobic environment.     

Insights into partially folded or unfolded States of metalloproteins from nuclear magnetic resonance

Nuclear magnetic resonance (NMR) provides detailed insights into the conformational features of unfolded and partially folded proteins. In the case of metalloproteins, special attention should be devoted to the characterization of the properties of the metal binding sites, and specific approaches need to be developed depending on the nature of the metal ion and its coordination environment. At the same time, metal-based NMR parameters may help in getting a better picture of the average structural properties of the metalloprotein. A critical evaluation of the limits of applicability of paramagnetic effects for solution structure determination in partially folded or unfolded proteins is presented. The coupling between NMR characterization of structure and dynamic of the polypeptide chain and of the metal environment provides insights into the stabilizing role of metal ions in metalloproteins. The overall approach is illustrated for some case examples of increasing flexibility obtained far from native conditions for cytochrome c and superoxide dismutase, two metalloproteins that have been extensively studied in our lab and whose misfolded forms may be relevant for important biological processes.     

Design, folding, and activities of metal-assembled coiled coil proteins

Metal ions serve many purposes in natural proteins, from the stabilization of tertiary structure to the direction of protein folding to crucial roles in electron transfer and catalysis. There is considerable interest in creating metal binding sites in designed proteins to understand the structural role of metal ions and to design new metalloproteins with useful functions. The de novo design of metalloproteins and the role of metals in the folding of designed proteins are reviewed here, with particular focus on the design, folding, and activities of the [M(bpy-peptide)(3)](2+) structure. This maquette is constructed by the covalent attachment of 2,2'-bipyridine to the N-termini of amphiphilic peptides, and it is assembled into a folded trimeric coiled coil by the addition of a six-coordinate transition metal ion and the resulting hydrophobic collapse of the peptides. The [M(bpy-peptide)(3)](2+) structure has been employed in diverse applications, ranging from electron transfer pathway studies to the study of optimal hydrophobic packing in a virtual library to the construction of receptors and biosensors.     

Metal and cofactor insertion

Cells require metal ions as cofactors for the assembly of metalloproteins. Principally one has to distinguish between metal ions that are directly incorporated into their cognate sites on proteins and those metal ions that have to become part of prosthetic groups, cofactors or complexes prior to insertion of theses moieties into target proteins. Molybdenum is only active as part of the molybdenum cofactor, iron can be part of diverse Fe-S clusters or of the heme group, while copper ions are directly delivered to their targets. We will focus in greater detail on molybdenum metabolism because molybdenum metabolism is a good example for demonstrating the role and the network of metals in metabolism: each of the three steps in the pathway of molybdenum cofactor formation depends on a different metal (iron, copper, molybdenum) and also the enzymes finally harbouring the molybdenum cofactor need additional metal-containing groups to function (iron sulfur-clusters, heme-iron).     

New force field parameters for metalloproteins I: Divalent copper ion centers including three histidine residues and an oxygen‐ligated amino acid residue

Transition metal ion complexation with proteins is ubiquitous across such diverse fields as neurodegenerative and cardiovascular diseases and cancer. In this study, the structures of divalent copper ion centers including three histidine and one oxygen‐ligated amino acid residues and the relative binding affinities of the oxygen‐ligated amino acid residues with these metal ion centers, which are debated in the literature, are presented. Furthermore, new force field parameters, which are currently lacking for the full‐length metal‐ligand moieties, are developed for metalloproteins that have these centers. These new force field parameters enable investigations of metalloproteins possessing these binding sites using molecular simulations. In addition, the impact of using the atom equivalence and inequivalence atomic partial charge calculation procedures on the simulated structures of these metallopeptides, including hydration properties, is described. © 2014 Wiley Periodicals, Inc.     

Metal and redox modulation of cysteine protein function

In biological systems, the amino acid cysteine combines catalytic activity with an extensive redox chemistry and unique metal binding properties. The interdependency of these three aspects of the thiol group permits the redox regulation of proteins and metal binding, metal control of redox activity, and ligand control of metal-based enzyme catalysis. Cysteine proteins are therefore able to act as "redox switches," to sense concentrations of oxidative stressors and unbound zinc ions in the cytosol, to provide a "storage facility" for excess metal ions, to control the activity of metalloproteins, and to take part in important regulatory and signaling pathways. The diversity of cysteine's multiple roles in vivo is equally as fascinating as it is promising for future biochemical and pharmacological research.     

Metallacyclopeptides: artificial analogues of naturally occurring peptides

Naturally occurring metalloproteins contain metal ions either to introduce a special reactivity or to stabilize a peptide structure. Since the early 1990s, chemists have been trying to use metal coordination for the fixation of short artificial peptides in well-defined cyclic structures. In this tutorial review a survey of the general approaches towards metallacyclopeptides as small cyclic peptide derivatives or as a part of a bigger alpha-helix (or beta-sheet) structure is given. In three case studies it is shown how naturally occurring compounds can be mimicked by metal coordination to non-natural peptide derivatives.     

Protein-Inspired Polymers with Metal-Site-Regulated Ordered Conformations

Metal ions play critical roles in facilitating peptide folding and inducing conformational transitions, thereby impacting on the biological activity of many proteins. However, the effect of metal sites on the hierarchical structures of biopolymers is still poorly understood. Herein, inspired by metalloproteins, we report an order-to-order conformational regulation in synthetic polymers mediated by a variety of metal ions. The copolymers are decorated with clinically available desferrioxamine (DFO) as an exogenous ligand template, which presents a geometric constraint toward peptide backbone via short-range hydrogen bonding interactions, thus dramatically altering the secondary conformations and self-assembly behaviors of polypeptides and allowing for a controllable β-sheet to α-helix transition modulated by metal–ligand interactions. These metallopolymers could form ferritin-inspired hierarchical structures with high stability and membrane activity for efficient brain delivery across the blood–brain barrier (BBB) and long-lasting magnetic resonance imaging (MRI) in vivo.     

Extension of QM/MM docking and its applications to metalloproteins

To overcome the limitation of conventional docking methods which assume fixed charge model from force field parameters, combined quantum mechanics/molecular mechanics (QM/MM) method has been applied to docking as a variable charge model and shown to exhibit improvement on the docking accuracy over fixed charge based methods. However, it has also been shown that there are a number of examples for which adoption of variable‐charge model fails to reproduce the native binding modes. In particular, for metalloproteins, previously implemented method of QM/MM docking failed most often. This class of proteins has highly polarized binding sites at which high‐coordinate‐numbered metal ions reside. We extend the QM/MM docking method so that protein atoms surrounding the binding site along with metal ions are included as quantum region, as opposed to only ligand atoms. This extension facilitates the required scaling of partial charges on metal ions leading to prediction of correct binding modes in metalloproteins. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009