Introduction 4708 2. Peptides and Silver 4709 2.1. Silver Binding to Amino Acids and Peptides 4709 2.1.1. Silver Binding to Amino Acids − Theory 4709 2.1.2. Silver Binding to Amino Acids − Experiment 4711 2.1.3. Silver Binding to Peptides 4711 2.2. Natural Peptides Involved in Metal Detoxification 4714 2.3. Peptides for the Formation of Silver Nanostructures 4716 2.3.1. Biomineralization of Silver by Means of Peptides 4716 2.3.2. Peptides as Structure-Determining Scaffolds in the Synthesis of Silver Nanostructures 4721 3. Bacteria and Silver 4722 3.1. Antimicrobial Properties of Silver-Containing Compounds 4722 3.1.1. Interactions with the Bacterial Cell Wall 4722 3.1.2. Interactions with DNA, Enzymes, and Membrane Proteins 4724 3.1.3. Generation of Reactive Oxygen Species 4725 3.2. Bacterial Resistance Mechanisms against Ag(I) 4726 3.2.1. Accumulation and Storage-Based Mechanism 4726 3.2.2. Efflux Pump-Based Mechanism 4727 3.3. Synthesis of Silver Nanoparticles by Means of Bacteria 4728 4. Silver-Based Biomaterials in the Medical Field 4730 4.1. Types of Silver-Containing Biomaterials 4731 4.1.1. Metallic Silver Coatings and Silver's Antimicrobial Efficiency 4731 4.1.2. Silver-Containing Nanocomposites 4732 4.1.3. Silver-Containing Polymers 4732 4.1.4. Surface Modification with Ionic Silver Compounds 4734 4.1.5. Hybrid Silver Materials − Synergistic Effects 4734 4.2. Deposition Processes 4735 4.3. Mechanical Properties 4736 5. Biocompatibility of Silver 4737 5.1. General Routes of Silver Exposure 4737 5.2. Exposure to Silver-Containing Medical Products 4737 5.2.1. Dermal Contact: Burn Wound Dressings 4737 5.2.2. Bone Contact: Orthopedic and Dental Implants and Bone-Filling Products 4738 5.2.3. Blood Contact: Implants Introduced into the Vascular System 4739 5.3. Effects of Silver Exposure on Tissues and Organs 4739 5.3.1. Acute and Chronic Toxicity of Silver 4740 5.3.2. Tissue and Organ Damages 4740 5.3.3. Cellular Uptake of Silver 4741 5.4. Toxic Effects of Silver Nanoparticles 4741 5.5. Silver Detoxification 4742 5.5.1. Sequestration of Silver Ions 4742 5.5.2. Silver Ion Transport by ATPase P-type Efflux Pumps 4743 6. Conflicting Evidence 4744 7. Conclusions 4744 Author Information 4744 Corresponding Author 4744 Notes 4744 Biographies 4745 Acknowledgments 4746 References 4746

Long-range electron transfer (ET) through proteins is a fundamental reaction in living organisms, playing a role in energy-conversion processes like photosynthesis [1a] and respiration [1b] as well as in enzymatic reactions. [1c] The mechanism of these ET processes is still a matter of controversy. Two cases are discussed, a bridge-mediated superexchange (single-step reaction) and a hopping mechanism (stepwise reaction). [2] Today, the hopping mechanism, where each step follows the Marcus rule, [3] is favored for long-range ET through peptides. [4] Nevertheless, for special conformations like a helices with their intramolecular hydrogen bonds, experiments on long-range ET have been discussed as single-step reactions. [5] However, quantum chemical calculations favor a multistep reaction also in a helices. [6] For the polyproline II helix (PPII helix), which does not have hydrogen bonds, a mechanistic transition between a singlestep and a stepwise reaction was observed when the number of the proline units between the electron donor and the electron acceptor is larger than 4. [7] Quantum chemical calculations explain the effect of peptide conformations on the distance influence of ET by a pathway model. [8] Recently it was shown that the rate also depends upon the direction of the ET process, demonstrating the important impact of dipole moments. [9] Another parameter influencing ET is the charge of ions bound as cofactors to the systems. [10] Such a Coulomb effect should also be of importance in peptides with unprotected amino or carboxylate groups that exist as ions under biological conditions. Herein we present our new results, which demonstrate that ET in peptides is indeed influenced by their charged termini.The investigations were carried out with our recently developed model peptides 1 in which ET occurs between the radical cation of a dialkoxyphenyl group (electron acceptor at the C-terminal end) and tyrosine as the electron donor at the N-terminal end. Halfway between the donor and the acceptor we introduced an amino acid with a side chain X. [11] These three amino acids were separated by sequences of three prolines (Scheme 1). If X is a side chain that can be oxidized by the electron acceptor, this central amino acid acts as a stepping stone for a hopping process (relay amino acid). [11] The structure of peptides 1 (in CH 3 CN/H 2 O 3:1) was characterized by their CD spectra as PPII helices. [12] Interestingly, the CD spectra remained unchanged when the temperature was varied between 20 8C and 80 8C, which supports the conformational stability of the peptides. These findings are in agreement with experimental and theoretical data from other polyproline systems. [13,14] In a PPII helix each of the triproline spacers corresponds to a distance of about 10 . [13,14] The triproline units thus separate the donor, the acceptor, and the relay amino acids, and act as a medium for the ET process. The 13 C NMR spectra [15,16] indicate that approximately 80 % of the proline peptide bonds adopt a trans conformat...

The life time of aromatic radical cations is limited by reactions like b-elimination, dimerization, and addition to the solvent. Here we show that the attachment of such a radical cation to the C-terminal end of an a-/3 10 -helical peptide further reduces its life time by two orders of magnitude. For PPII-helical peptides, such an effect is only observed if the peptide contains an adjacent electron donor like tyrosine, which enables electron transfer (ET) through the peptide. In order to explain the special role of a-/3 10 -helical peptides, it is assumed that the aromatic radical cation injects a positive charge into an adjacent amide group. This is in accord with quantum chemical calculations and electrochemical experiments in the literature showing a decrease in the amide redox potentials caused by the dipole moments of long a-/3 10 -helical peptides. Rate measurements are in accord with a mechanism for a multi-step ET through a-/3 10 -helical peptides that uses the amide groups or H-bonds as stepping stones.

Electron transfer (ET) is a basic chemical reaction, which involves radicals and radical ions. In all living organisms, ETs through peptides and proteins are vital for energy conversion and metabolic processes. In several cases, distances are so long that ET cannot occur as a single‐step reaction, and the process is a result of a multistep reaction, where the charge hops between relay stations. Each of the hopping steps obeys the Marcus theory with its strong distance dependence, but the overall process is described by the weak distance dependency of diffusion. Aromatic and sulfur‐containing aliphatic amino acids are relay amino acids, and for special peptide conformations also the amide bonds might act as stepping stones. ET rates depend on peptide conformations, redox potentials, dipole moments, charges, and proton transfer processes. In addition to its fundamental biological importance, ET also starts to play a role as electronic material. In this article, the basic principles, ET in biological systems, and the possible applications in materials science are presented and discussed.

Artificial implants and biomaterials lack the natural defense system of our body and, thus, have to be protected from bacterial adhesion and biofilm formation. In addition to the increasing number of implanted objects, the resistance of bacteria is also an important problem. Silver ions are well‐known for their antimicrobial properties, yet not a lot is known about their mode of action. Silver is expected to interact on many levels, thus the development of silver resistance is very difficult. Nevertheless, some bacteria are able to resist silver, even at higher concentrations. One such defense mechanism of bacteria against heavy‐metal intoxication includes an efflux system. SilE, a periplasmic silver‐binding protein that is involved in this defense mechanism, has been shown to possess numerous histidine functions, which strongly bind to silver atoms, as demonstrated by ourselves previously. Herein, we address the question of how histidine binds to silver ions as a function of pH value. This property is important because the local proton concentration in cells varies. Thus, we solved the crystal structures of histidine–silver complexes at different pH values and also investigated the influence of the amino‐acid configuration. These results were completed by DFT calculations on the binding strength and packing effects and led to the development of a model for the mode of action of SilE.