Functional Metallosupramolecular Materials: Volume 15 (Smart Materials Series) - Hardcover

Hardcover

ISBN 10: 1782620222 ISBN 13: 9781782620228

Publisher: Royal Society of Chemistry, 2015

Synopsis

A comprehensive overview of different metallosupramolecular systems and their applications in magnetic, photonic and electronic materials.

About this title

From the Back Cover

There is great interest in metallosupramolecular materials because of their use in magnetic, photonic and electronic materials. Functional Metallosupramolecular Materials focuses on the applications of these materials covering the chemistry underlying the synthesis of a variety of ligands to coordinate various metal ions and the generation of 2D and 3D materials based on these constructs.

The book starts by looking at different metallosupramolecular systems including naturally occurring functional metallosupramolecular materials; DNA-based metallosupramolecular materials; metallopolymers; metallogels as well as functional materials based on MOFs. Subsequent chapters then systematically cover the different applications such as molecular computation, spin-crossover, light harvesting and as photocatalysts for the production of solar fuels.

The book provides an overview of functional metallosupramolecular materials that will be of interest to graduate students, academics and industrial chemists interested in supramolecular chemistry, materials science and the materials applications.

From the Inside Flap

There is great interest in metallosupramolecular materials because of their use in magnetic, photonic and electronic materials. Functional Metallosupramolecular Materials focuses on the applications of these materials covering the chemistry underlying the synthesis of a variety of ligands to coordinate various metal ions and the generation of 2D and 3D materials based on these constructs.

The book starts by looking at different metallosupramolecular systems including naturally occurring functional metallosupramolecular materials; DNA-based metallosupramolecular materials; metallopolymers; metallogels as well as functional materials based on MOFs. Subsequent chapters then systematically cover the different applications such as molecular computation, spin-crossover, light harvesting and as photocatalysts for the production of solar fuels.

The book provides an overview of functional metallosupramolecular materials that will be of interest to graduate students, academics and industrial chemists interested in supramolecular chemistry, materials science and the materials applications.

Excerpt. © Reprinted by permission. All rights reserved.

Functional Metallosupramolecular Materials

By John G. Hardy, Felix H. Schacher

The Royal Society of Chemistry

Copyright © 2015 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78262-022-8

Contents

Chapter 1 Interaction of Metal Ions with Proteins as a Source of Inspiration for Biomimetic Materials Andrew M. Smith, 1, 
Chapter 2 DNA-Based Metallosupramolecular Materials Janane Rahbani, Kimberly Metera and Hanadi F. Sleiman, 32, 
Chapter 3 Constitutionally Dynamic Metallosupramolecular Systems Mihail Barboiu, 70, 
Chapter 5 Recent Advances in Immobilized Ferrocene-Containing Polymers Markus Gallei and Johannes Elbert, 120, 
Chapter 6 Metallosupramolecular Soft Materials: Metallogels Charlotte Po and Vivian Wing-Wah Yam, 149, 
Chapter 7 Metal-Organic Frameworks as Chemical Sensors Nolan W. Waggoner, Alisha M. Bohnsack and Simon M. Humphrey, 192, 
Chapter 8 Anchoring Metallosupramolecular Materials on Solid Substrates: Specific Surface-Molecule Interactions and Self-Assembly Giuseppina Pace and Artur R. Stefankiewicz, 246, 
Chapter 9 Metallosupramolecular Materials for Electronic Applications: Molecular Boolean Computation Brian Daly, Jue Ling and A. Prasanna de Silva, 269, 
Chapter 10 Metallosupramolecular Materials for Magnetic Applications: Spin-Crossover Suzanne Neville, 290, 
Chapter 11 Metallosupramolecular Materials for Energy Applications: Light Harvesting Vakayil K. Praveen and Ayyappanpillai Ajayaghosh, 318, 
Chapter 12 Metallosupramolecular Assemblies for Application as Photocatalysts for the Production of Solar Fuels Danilo Dini, Mary T. Pryce, Martin Schulz and Johannes G. Vos, 345, 
Subject Index, 397, 

CHAPTER 1

Interaction of Metal Ions with Proteins as a Source of Inspiration for Biomimetic Materials

ANDREW M. SMITH

1.1 Introduction

Nature utilises proteins to fulfil a range of functions from catalysing reactions, storage and transfer of energy to acting as structural supports. Proteins are, at the most basic level, polymers made up of a specific sequence of amino acids; this is known as the primary structure. These polymer chains have the potential to form highly complex structures where the individual amino acids interact to form specific folds, such as α-helices and β-sheets, known as the protein's secondary structure. These individual secondary structure units combine to give the protein fold, or tertiary structure. Individual proteins can interact with other proteins and molecules to give the supramolecular structure, which is the quaternary structure. The information that determines how the protein folds and interacts is encoded in the amino acid side chains and these are also responsible for the catalytic function of enzymes. The side chains of the twenty naturally occurring (canonical) amino acids cover a wide swathe of interactions including hydrophobic, hydrophilic, ionic and covalent bonds, however, there is a limit to what can be done using the canonical amino acids; as a consequence, nature has evolved to use inorganic components within the organic proteins to extend their functionality and facilitate reactions that would not be feasible using amino acids alone. For some functions, proteins have evolved to incorporate cofactors to increase the variety or efficiency of their functions. These cofactors can be organic or inorganic; here we are interested in the latter. Inorganic cofactors can be as simple as metal ions that are coordinated by amino acid side chains to complex organic non-protein groups that coordinate the metal ions. These metal ions are used for a variety of functional reasons, from aiding in the formation of the correct protein fold to forming the active site of an enzymatic reaction. The variety of metals incorporated in proteins is also very broad with a range of valences of metals such as iron, copper, zinc, magnesium, nickel, molybdenum, and manganese being seen in humans alone. The degree of variety is also increased when organic groups such as haems are included as well as cases of multiple metal ion clusters.

The first thing to bear in mind with the involvement of metal ions with proteins is that the concentration of each metal ion is maintained in cells and organelles within a specific range dependent on the cells. If metal ions exceed their normal levels then they can bind to additional sites as well as cause the displacement of other metal ions, resulting either in a change in specificity and reactivity or deactivation of the protein. The concentration ranges of free divalent metal ions is roughly based on the binding affinities of the metal ions, with Zn(II) being the strongest binder, and if sufficiently high concentrations are used, it will bind to most proteins. For the purpose of the discussions here, the interactions of physiologically relevant levels will be discussed.

Metal ions are involved in an extremely wide range of proteins, with over half of all proteins being metallo-proteins including all types of enzymatic reactions as well as being involved in electron transport chains. They are also involved in the formation of extracorporeal structures such as holdfast mechanisms, silks, and glues. Additionally, metal ions are also involved in disease states, such as neurodegenerative diseases involving the formation of amyloid plaques. Due to the extremely wide breadth of the involvement of metal ions, this chapter will give a general overview and pick a few examples to go into more detail.

First, we will look at metal ions in the active site of enzymes covering a few examples and cover different metal ions as well as multiple metal ion clusters. We will then move on to the use of metal-containing organic cofactors, such as haem, and the variety of functions such a structure can fulfil. We will then discuss the use of metal ions in structural proteins both in the formation of the structure and also in its interactions. Finally, we will have a look at the influence of metal ions on protein folding and misfolding and its involvement in neurodegenerative diseases as well as anti-microbial peptides.

1.2 Enzymes

Enzymes are the molecular machines of life as they catalyse an extremely wide range of reactions with varying efficiencies and specificities. There are an extremely wide range of proteins that contain metal ions; these can generally be split into two main groups, those which have inorganic cofactors, where the metal ion is directly bound by the protein side chains and those that have an organic cofactor, a non-protein group for example a haem group that coordinates the metal ions.

1.2.1 Single Metal Ion Enzymes

1.2.1.1 Zinc Dependent Enzymes

Zinc was the first of the metal ions to be recognised as essential for life and in 1939 the first enzyme, erythrocyte carbonic anhydrase, was discovered where zinc was essential for activity. There are now in the order of 3000 zinc proteins and they have functionalities across all classes of enzymes. One of the major discoveries was the "zinc finger" which was first identified in the Xenopus laevis transcription factor IIIA, which contains nine repetitive sequences of cysteine and histidine residues that coordinate nine zinc ions in the protein. The characteristic pattern of cysteine and histidine residues separated by spacers of amino acids (X) CXaCXbHXcH which can coordinate metal ions has allowed the identification of these small domains in many proteins. The sequence forms a small elongated domain (Figure 1.1) where the Zn(II) acts as the pinning point at the base of the loop that forms the finger, hence its generic name of zinc finger. In the case of the initially identified protein, it can interact with the major groove of DNA. While the initial zinc finger discovery was for DNA binding, and many of the related proteins also have this role, it has also been shown to enable binding of proteins and lipids.

In the case of zinc finger proteins, the zinc does not have a catalytic function but a purely structural role which is nonetheless essential for the binding and hence activity of such proteins. Zn(II) is the tightest binding metal ion to proteins and it is generally accepted that there is no activation of Zn(II) enzymes, rather that they are controlled through inhibition mechanisms. Zinc is also known to bind and inhibit a number of enzymes, including zinc metalloproteases. For example, there is a secondary non-active zinc binding site in carboxypeptidase A that is 3.3 Å from the zinc active site and has a Ki of 0.7 µM. In the case of the human receptor protein tyrosine phosphatase β, Zn(II) has a Ki of 21 pM, while for bovine dimethylarginine dimethylami-nohydrolase (isoform 1), it has a Ki of 4 nM. Thus enzymes such as these may be inhibited by Zn(II) at physiological conditions and only activated by removal of the Zn(II). However, the identification of such enzymes is difficult as the vast majority of enzyme studies utilise enzymes that are purified from a heterologous system rather than their host tissues. As a large number of enzymes have catalytic active sites that incorporate cysteine, histidine, glutamic/aspartic acid, it is feasible that the active site can be occupied by a metal ion. The zinc level within cells is kept remarkably low at around 1 nM, but it is known to fluctuate within cells due to a whole range of conditions dependent on cell type and zinc ions are stored and released both intra- and inter-cellularly. In pancreatic islet β cells, the zinc(II) ions participate in the formation of insulin into granules for storage and are secreted along with insulin. Thus the concentrations of zinc can have a great effect on cellular activities. One cellular component that is known to be involved in the regulation of zinc is thionein or metallothionein which binds up to seven Zn(II) ions. It has been shown that this thionein can efficiently remove the Zn(II) ions from inhibited enzymes such as glyceraldehyde 3-phosphate dehydrogenase, which recovers activity from inhibition within seconds of addition of thionein. While it has been shown for multiple enzymes that thionein does not remove the Zn(II) ions tightly bound in the catalytic sites of zinc metalloproteins, for example, with a 20-fold excess of thionein, alcohol dehydrogenase loses only marginal activity.

Thus we can see that zinc has a wide range of functions within proteins and can act to form specific structures and as both an inhibitor and the catalytic centre of enzymes. This breadth of functions for zinc is not unique. Rather than go through each possible metal ion, we will now look at specific reactions or functions and how the metal ions are utilised by proteins.

1.2.1.2 Non-Haem Oxygenases

There are several classes of non-haem oxygenases that utilise iron in the catalytic core of the enzyme, many of which utilise additional cofactors in the reaction. One class of these enzymes are the aromatic amino acid hydroxylases (AAAHs), which have a tetrahydropterin cofactor and are involved in the synthesis of the aromatic amino acids. The original enzyme appears to have developed in prokaryotes as a phenylalanine hydroxylase, which has then evolved in eukaryotes as hydroxylases for the other two aromatic amino acids. All the AAAHs feature a facial triad of two histidine residues and a glutamic acid residue, a common feature of Fe(II) non-haem oxygenases; the other three ligands to Fe(II) are water, due to it being solvent exposed in mammalian AAAHs. Mutation of any of these described conserved residues to an alanine residue results in the Fe(II) being absent thus inactivating the enzyme. A study into tryptophan hydroxylase involved mutating the histidine residues to glutamate and glutamine, and the glutamate residues to histidine and glutamine respectively. This experiment showed that while in some cases the Fe(II) binding is retained, the activity of the enzyme is removed in all cases. The enzymes require that all three catalytic components — pterin, amino acid substrate and dioxygen — are bound prior to the start of the catalytic reaction (Figure 1.2). The exact order of binding is unclear, but it appears that O2 binds reversibly as the last binding step prior to reaction.

Another non-haem iron oxygenase is the 1-aminocyclopropane-1-carboxylic acid (ACC) oxygenase, which is the last step in the synthesis of ethylene in plants. This is an important enzyme as the levels of ethylene produced by plants as a result of stress can produce deleterious effects in the plants. As with the AAAHs, the Fe(II) is coordinated by two histidines and in this case an aspartate instead of a glutamate, with ascorbate and CO2 or bicarbonate needed alongside ACC. In this case it is proposed that ascorbic acid or ACC binds first, followed by dioxygen binding as the second step in binding. The exact role of ascorbate in this reaction is unclear and it has been proposed that it binds away from the Fe(II) centre with other amino acids in the catalytic site; it has also been classed as a co-substrate and effector. This highlights that with some enzymatic reactions, the sequence of binding of substrate, cofactors and ligands is sometimes hard to determine but is still important for the catalytic reaction.

1.2.2 Binuclear Metallohydrolases

Binuclear metal enzymes contain two metal ions that are either coordinated together or through a bridging ligand. In some cases these enzymes also contain additional metal ions or even additional metal ion active sites. We are interested in the many cases where the close proximity of the two metal ions is utilised in the enzymatic reaction that they catalyse. While it is possible that the two metal ions are the same, it is also possible to have metal centres containing different valence metal ions and also completely different metal ions. As a consequence of having multiple metal ions, often in different states, the catalytic reaction can become quite complex; this is further complicated by the fact that both metal sites are not always occupied throughout the catalytic cycle. There has been extensive research into various binuclear metallohydrolase groups and here we will present two examples, however, there is a large range of additional examples that we will not cover for the sake of brevity.

1.2.2.1 Purple Acid Phosphatases

Purple acid phosphatases (PAPs) are the only examples of binuclear hydrolases where it has been shown that a heterovalent catalytic site is necessary for activity. These phosphatases have earned their name due to the characteristic colour of the enzymes. This colour comes from a conserved tyrosine ligand to a ferric ion in the active site of the protein. These enzymes have been found in mammals, plants, and a limited number of micro-organisms. Mammalian PAPs are approximately 35 kDa and are highly conserved with 85% identity. They are proposed to have roles in iron transport, the generation of reactive oxygen species and bone resorption. On the other hand, plant PAPs are mostly homodimers with a subunit mass of approximately 55 kDa, but some heterodimers have also been reported. The homodimeric PAPs share roughly 65% identity but the identity between mammalian and plant PAPs is low. In plants, PAPs are proposed to have roles in the generation of reactive oxygen species and phosphate metabolism.

The active site of PAPs consists of two metal binding sites, a trivalent and a divalent metal ion site. The trivalent site is typically occupied by Fe(III), but in at least one case, that of the PAP from sweet potato, this can be replaced with Mn(II), resulting in a loss of the purple colour. The trivalent metal ion is coordinated to a conserved deprotonated tyrosine residue, as well as a histidine residue and two aspartic acid residues, one of which also coordinates the other metal site. The divalent metal ion is coordinated by two histidines, an asparagine and the shared aspartate residue. In mammals, the divalent metal site is Fe(II) which is essential for the functioning of the enzyme. In plants, the divalent site is usually Zn(II) or Mn(II) and in at least one case Fe(II), a recombinant isoform from sweet potatoes. There are additional ligands to the metal ions but these vary depending on the system and the study, however, a general reaction mechanism for the PAPs has been developed from a range of spectroscopic and crystal structure studies. This reaction mechanism is illustrated in Figure 1.3. The first step is substrate binding creating a hydrogen bonding network, followed by the rearrangement of the substrate so that it is coordinated to the divalent ion so that it can undergo a nucleophilic attack by a solvent-derived hydroxyl ion, or the metal ion bridging hydroxide (µ-OH), it is not clear which. Following the nucleophilic attack and hydrolysis of the substrate ester bond, the alcohol leaving group is released. The secondary product of the hydrolysis of the phosphate group remains bound to the active site. The regeneration of the active site is not clearly understood as it requires the removal of the phosphate group and potentially the regeneration of the µ-OH bridging the metal ions. One suggested mechanism, illustrated in Figure 1.3, is the coordination of a water molecule to the Fe(III) centre and then the regeneration of the µ-OH bridge, which would weaken the bonding of the phosphate leading to its release and return to the resting state.64 There are two nucleophiles in the overall reaction as determined by the sequential cleavage of the ester bonds in a diester substrate65 so that both are used but it is not clear in which order.

1.2.2.2 Metallo-β-lactamases

β-Lactams are one of the most important groups of antibiotics that are currently available to deal with bacterial infections. However, over time bacteria have evolved that possess resistance to this class of antibiotics. This resistance has been achieved through a number of methods, the most important of which has been through the evolution of enzymes that can hydrolyse these antibiotics, the β-lactamases. Three of the four classes of β-lactamases, possess an essential serine residue in the catalytic centre. However, based on sequence analysis, the fourth class, class B β-lactamases, have an ion centre that requires either one or two Zn(II) ions bound in the active site to be functional and a αββα fold. These are termed the metallo-β-lactamases (MβLs); they share a common fold and a small amount of sequence homology, but have been split up into three subclasses. The MβLs are important as within their group they are resistant to all β-lactamase inhibitors and are capable of cleaving all β-lactam antibiotics including the carbapenems which are regarded as the antibiotic of last resort. B1 is the largest sub-class and can be coded either on chromosomes or on mobile elements that enable them to disseminate easily. β-Lactamases in class B1 and B3 have very broad specificity being able to inactivate all bicyclic β-lactams, while B2 β-lactamases are all known to be carbapenemases. B1 and B3 type MβLs have three histidine residues coordinating the first Zn(II) site, Zn1, while the B2 type MβLs have replaced one of the histidine residues with an asparagine (Figure 1.4). The second metal binding site is conserved between the B1 and B2 type MβLs consisting of an aspartate, histidine and a cysteine residue, while the B3 type MβLs replace the cysteine with another histidine residue. In the case of the B2 type MβLs, the second metal site is not occupied in the catalytic form of the protein (Figure 1.4). However, it is not clear whether this is also the case for the other types of MβLs. The role of the second zinc ion in the reactivity of the MβLs is also not clear to the extent that researchers are uncertain whether it is completely necessary or not. As there are differences in the metal centres of the subtypes of these enzymes, it is not completely clear how the exact reactive mechanism of these enzymes functions and several slightly different mechanisms for the reactivity of these proteins have been suggested. The enzymes are a subclass of the metallo-proteases and thus their reaction mechanisms are all centred around the cleavage of the C–N bond in the β-lactam. The mechanisms described for these enzymes have looked at both mono- and binuclear enzymatic reactions. For B1 class MβLs, it has been proposed that with a single Zn(II), the reaction mechanism is similar to single Zn(II) peptidases where, after substrate binding, a deprotonated zinc-bound water molecule attacks the carbonyl centre forming a negatively charged tetrahedral intermediate, which is stabilised through interactions with the Zn(II). The aspartate can then donate a hydrogen to the nitrogen resulting in the cleavage of the C–N bond. The exact order of these last steps in the breakage of the C–N bond is not clear, and it may be that the bond is cleaved before the hydrogen is donated by the aspartate residue. Whether the second zinc ion is necessary is also unclear; some studies have shown that at physiological conditions, the second Zn site is only partially occupied and also that it is not always necessary for the highest reactivity, but this is dependent on the study.

(Continues...)

Excerpted from Functional Metallosupramolecular Materials by John G. Hardy, Felix H. Schacher. Copyright © 2015 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Edition details

• Publisher: Royal Society of Chemistry
• Publication date: 2015
• Language: English
• ISBN 10: 1782620222
• ISBN 13: 9781782620228
• Binding: Hardcover
• Number of pages: 416
• Editor: John George Hardy