Protein misfolding in cells is avoided by a network of protein chaperones that detect misfolded or partially folded species. When proteins escape these control systems, misfolding may result in protein aggregation and amyloid formation. We here show that aggregation of the amyloidogenic protein α-synuclein (αS), the key player in Parkinson's disease, is controlled by the copper transport protein Atox1 in vitro. Copper ions are not freely available in the cellular environment, but when provided by Atox1, the resulting copper-dependent ternary complex blocks αS aggregation. Because the same inhibition was found for a truncated version of αS, lacking the C-terminal part, it appears that Atox1 interacts with the N-terminal copper site in αS. Metal-dependent chaperoning may be yet another manner in which cells control its proteome.

This is a tour of a physical chemist through 65 years of protein chemistry from the time when emphasis was placed on the determination of the size and shape of the protein molecule as a colloidal particle, with an early breakthrough by James Sumner, followed by Linus Pauling and Fred Sanger, that a protein was a real molecule, albeit a macromolecule. It deals with the recognition of the nature and importance of hydrogen bonds and hydrophobic interactions in determining the structure, properties, and biological function of proteins until the present acquisition of an understanding of the structure, thermodynamics, and folding pathways from a linear array of amino acids to a biological entity. Along the way, with a combination of experiment and theoretical interpretation, a mechanism was elucidated for the thrombin-induced conversion of fibrinogen to a fibrin blood clot and for the oxidative-folding pathways of ribonuclease A. Before the atomic structure of a protein molecule was determined by x-ray diffraction or nuclear magnetic resonance spectroscopy, experimental studies of the fundamental interactions underlying protein structure led to several distance constraints which motivated the theoretical approach to determine protein structure, and culminated in the Empirical Conformational Energy Program for Peptides (ECEPP), an all-atom force field, with which the structures of fibrous collagen-like proteins and the 46-residue globular staphylococcal protein A were determined. To undertake the study of larger globular proteins, a physics-based coarse-grained UNited-RESidue (UNRES) force field was developed, and applied to the protein-folding problem in terms of structure, thermodynamics, dynamics, and folding pathways. Initially, single-chain and, ultimately, multiple-chain proteins were examined, and the methodology was extended to protein–protein interactions and to nucleic acids and to protein–nucleic acid interactions. The ultimate results led to an understanding of a variety of biological processes underlying natural and disease phenomena.

The determination of a novel protein structure by X-ray diffraction is seldom straightforward. Three hurdles present themselves (i) the protein must be purified in sufficient quantity to allow crystallization trials, (ii) crystals must be grown to adequate size and must diffract to a resolution that will allow atomic detail to be revealed, and (iii) phases must be determined for the diffracted X-ray beams in order that an initial electron-density map may be calculated.

Mass spectrometric analysis of organic compounds was in the early 1950s done mostly for quantitative determination of petroleum products. The use of the mass spectrometer for qualitative analysis of solid organic material samples was shown by O'Neil & Wier (1951) and since then a continuous increase in mass spectrometric studies of different classes of organic compounds has been noted. After the gas chromatograph was developed by James & Martin (1952) the quantitative analysis of complex mixtures of organic compounds was possible and after a few years the gas chromatographic method was considered as routine. The first connection of a gas chromatograph (GC) to a mass spectrometer (MS) was made by Holmes & Morell (1957). They studied gases using a splitter system where only a small part or less than 1% of the effluent from a packed column was transferred to the ion source of the mass spectrometer. The next step in GC—MS development was made by Gohlke (1959), who studied compounds of low molecular weight using capillary column directly connected to a time-of-flight mass spectrometer. This was possible due to the fact that the carrier gas flow rate could be limited to about 1 ml/min. To avoid the sample loss resulting from using a packed column with the splitter system a jet molecular separator was constructed as an interphase between the packed column and a mass spectrometer with magnetic sector analyser (Ryhage, 1964). Mixtures of fatty acids and of hydrocarbons with a molecular weight of up to about 420 were studied. In this study spectra were taken at irregular intervals.

The past decade has witnessed significant developments in molecular biology techniques, fluorescent labeling, and super-resolution microscopy, and together these advances have vastly increased our quantitative understanding of the cell. This detailed knowledge has concomitantly opened the door for biophysical modeling on a cellular scale. There have been comprehensive models produced describing many processes such as motility, transport, gene regulation, and chemotaxis. However, in this review we focus on a specific set of phenomena, namely cell polarization, F-actin waves, and cytokinesis. In each case, we compare and contrast various published models, highlight the relevant aspects of the biology, and provide a sense of the direction in which the field is moving.

Synthetic peptide and peptido-mimetic filaments and tubes represent a diverse class of nanomaterials with a broad range of potential applications, such as drug delivery, vaccine development, synthetic catalyst design, encapsulation, and energy transduction. The structures of these filaments comprise supramolecular polymers based on helical arrangements of subunits that can be derived from self-assembly of monomers based on diverse structural motifs. In recent years, structural analyses of these materials at near-atomic resolution (NAR) have yielded critical insights into the relationship between sequence, local conformation, and higher-order structure and morphology. This structural information offers the opportunity for development of new tools to facilitate the predictable and reproducible de novo design of synthetic helical filaments. However, these studies have also revealed several significant impediments to the latter process – most notably, the common occurrence of structural polymorphism due to the lability of helical symmetry in structural space. This article summarizes the current state of knowledge on the structures of designed peptide and peptido-mimetic filamentous assemblies, with a focus on structures that have been solved to NAR for which reliable atomic models are available.

The ribosome is a dynamic machine that undergoes many conformational rearrangements during the initiation of protein synthesis. Significant differences exist between the process of protein synthesis initiation in eubacteria and eukaryotes. In particular, the initiation of eukaryotic protein synthesis requires roughly an order of magnitude more initiation factors to promote efficient mRNA recruitment and ribosomal recognition of the start codon than are needed for eubacterial initiation. The mechanisms by which these initiation factors promote ribosome conformational changes during stages of initiation have been studied using cross-linking, footprinting, site-directed probing, cryo-electron microscopy, X-ray crystallography, fluorescence spectroscopy and single-molecule techniques. Here, we review how the results of these different approaches have begun to converge to yield a detailed molecular understanding of the dynamic motions that the eukaryotic ribosome cycles through during the initiation of protein synthesis.

Condensation and faithful separation of the genome are crucial for the cellular life cycle. During chromosome segregation, mechanical forces generated by the mitotic spindle pull apart the sister chromatids. The mechanical nature of this process has motivated a lot of research interest into the mechanical properties of mitotic chromosomes. Although their fundamental mechanical characteristics are known, it still remains unclear how these characteristics emerge from the structure of the mitotic chromosome. Recent advances in genomics, computational and super-resolution microscopy techniques have greatly promoted our understanding of the chromosomal structure and have motivated us to review the mechanical characteristics of chromosomes in light of the current structural insights. In this review, we will first introduce the current understanding of the chromosomal structure, before reviewing characteristic mechanical properties such as the Young's modulus and the bending modulus of mitotic chromosomes. Then we will address the approaches used to relate mechanical properties to the structure of chromosomes and we will also discuss how mechanical characterization can aid in elucidating their structure. Finally, future challenges, recent developments and emergent questions in this research field will be discussed.

The ability to control the movement of molecules is both fascinating scientifically as well as being critically important to the well-being of our planet and its people. In particular, the sustained release of molecules over prolonged periods at controlled rates has had and will continue to have enormous implications for the delivery of substances in medicine, agriculture, the environment, nutrition, aquaculture, household consumer products, and numerous other areas. This field is advancing at a rapidly accelerating pace. In this article, I largely discuss our own work, starting 45 years ago, in enabling the controlled release of macromolecules from biocompatible polymers. I also discuss the synthesis of novel materials to affect molecular movement and I then examine external approaches for controlling the movement of molecules through materials, using forces such as electric, acoustic, and magnetic fields. I further discuss approaches for controlling molecular movement through physiologic barriers, such as the skin, lung, and intestine. Finally, I outline several future areas of this field, including how it can affect the developing world, the ability to control the movement of molecules into mammalian cells, and the design of intelligent approaches to control molecular delivery.

Left–right (l–r) symmetry breaking and the establishment of asymmetric animal body plan during embryonic development are fundamental questions in nature. The molecular basis of l–r symmetry breaking of snails is a fascinating topic as it is determined by a maternal single handedness-determining locus at a very early developmental stage. This perspective describes the current state of the art of the chiromorphogenesis, mainly based on our own work, i.e. the first step of l–r symmetry breaking, as proven by our “Mechanogenetics”, before the start of zygotic gene expression, transfer of chirality information to the cell-fate determining stage, and the expression of nodal at the blastula stage. The Nodal signalling pathway is a common mechanism in vertebrates’ chiromorphogenesis in later development. Studies on snails, especially Lymnaea (L.) stagnalis, shall give important insights into the molecular basis of chiromorphogenesis not only in Lophotrochozoa but in vertebrates as well.

Selection in biochemical synthesis processes is a very important task: processes as protein or nucleic acid synthesis must be very accurate although the cell abounds with closely related molecules which, intuitively, should be difficult to distinguish. The mechanisms of selection and the underlying processes have been extensively studied in the last years, and the ideas have been developed into mathematical models to visualize the potentials of recognition and error correction. There are several aspects on this, the main aspect of the present work being the important fact that the cell must pay for the increased accuracy in terms of available free energy: processes are driven from equilibrium, and do away with appreciable dissipation.

The advent of methods for forming and studying lipid bilayer membranes (Mueller et al. 1962; Hanai et al. 1964) opened the way for some fifteen years ofintensive and productive study of the properties of lipid soluble ions and ion carriers. I expect that none will dissent from the view that Peter Läuger and his associates, including R. Benz and G. Stark, did more than any other research group to advance the study of the mechanism of the charge transfer. Between 1970 and 1981 they published more than 25 substantial contributions. Thus it is appropriate that this memorial issue should contain a short review of this subject. As I have the highest regard for their work I was very pleased to be asked to write such a chapter. There is little point in providing another general survey because Läuger's group published reviews at the end of this period (Benz et al. 1980; Läuger et al. 1981) and I also reviewed the field at length (Hladky, 1979a). Instead I would like to consider the three cornerstone papers of 1971, some of the difficulties that arose from those papers, how they were overcome, and three aspects of the description that are still incomplete.

In 1968 it was discovered that mercury could be biomethylated to give methylmercury as the major product (Wood, Kennedy & Rosen, 1968; Jensen & Jernelöv, 1969). This discovery has proved to be important in two respects: (a) it provided us with the recognition that biological systems are capable of synthesizing very toxic organometallic compounds from relatively innocuous inorganic precursors, and (b) it opened the door to the study of organometallic compounds produced by biological mechanisms in the aqueous environment.

Nuclear magnetic resonance is the most important form of molecular spectroscopy in chemistry and biochemistry but it is normally blind to chirality. It was predicted in 2004 that precessing nuclear spins in chiral molecules in a liquid in a strong magnetic field induce a rotating electric polarization that is of opposite sign for enantiomers. This polarization arises from the distortion of the electronic structure by the nuclear magnetic moment in the presence of the strong magnetic field and is equivalent to the linear effect of an electric field on the nuclear shielding tensor. The polarization is strongly enhanced in dipolar molecules through the partial orientation of the permanent dipole through the antisymmetric part of the nuclear magnetic shielding tensor. Alternatively, an applied electric field will induce a chirally sensitive magnetization perpendicular to the field and to the nuclear spin. Progress towards the experimental realization of chiral discrimination by NMR is assessed.

The use of traditional Western concepts of disease (i.e. the ‘germ’ theory) has guided the use of scientific knowledge and technologies in the Control of acute infectious diseases (Gori & Peters, 1975; Trosko & Chang, 1978c). The intervention of all sorts of technologies has prolonged the life expectancy, allowing more people to reach the limit of what appears to be a rather fixed life-span (Hayflick, 1976). At the same time, human beings have used technologies to alter out dependence on the natural enviroment We intervene on many levels to minimize threats to our dependence on natural forces for food (e.g. agricultural technology, food additives), for water (e.g. wells or dams), for health (e.g. instituting sanitary measures or using drugs), for protection against the elements (e.g. wearing clothes, building homes with heaters and air conditioners) and for pleasure (e.g. snowmobiles, etc.). It is now extremely clear that much of the ‘effluents of our technological affluence’ can be harmful to living systems.

Exposure to various chemicals, either due to occupation or lifestyle, is considered to be a major contributing factor to tumour formation in man (Higginson, 1969; Doll and Peto, 1981). An important and prevalent class of potent carcinogenic compounds present in he environment is polycyclic aromatic hydrocarbons (PAHs), which are found in various petroleum and combustion products derived from heat and power generation and motor vehicle exhausts (Baum, 1978). Furthermore, since PAHs are generally formed by pyrolysis of organic matters such as tobacco smoking and certain procedures of food preparation, the PAH exposure to humans is extensive.

Flagellar dyneins are the molecular motors responsible for producing the propagating bending motions of cilia and flagella. They are located within a densely packed and highly organised super-macromolecular cytoskeletal structure known as the axoneme. Using the mesoscale simulation technique Fluctuating Finite Element Analysis (FFEA), which represents proteins as viscoelastic continuum objects subject to explicit thermal noise, we have quantified the constraints on the range of molecular conformations that can be explored by dynein-c within the crowded architecture of the axoneme. We subsequently assess the influence of crowding on the 3D exploration of microtubule-binding sites, and specifically on the axial step length. Our calculations combine experimental information on the shape, flexibility and environment of dynein-c from three distinct sources; negative stain electron microscopy, cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET). Our FFEA simulations show that the super-macromolecular organisation of multiple protein complexes into higher-order structures can have a significant influence on the effective flexibility of the individual molecular components, and may, therefore, play an important role in the physical mechanisms underlying their biological function.

Quantitative parameters for a two-state cooperative transition in duplex DNAs were finally obtained during the last 5 years. After a brief discussion of observations pertaining to the existence of the two-state equilibrium per se, the lengths, torsion, and bending elastic constants of the two states involved and the cooperativity parameter of the model are simply stated. Experimental tests of model predictions for the responses of DNA to small applied stretching, twisting, and bending stresses, and changes in temperature, ionic conditions, and sequence are described. The mechanism and significance of the large cooperativity, which enables significant DNA responses to such small perturbations, are also noted. The capacity of the model to resolve a number of long-standing and sometimes interconnected puzzles in the extant literature, including the origin of the broad pre-melting transition studied by numerous workers in the 1960s and 1970s, is demonstrated. Under certain conditions, the model predicts significant long-range attractive or repulsive interactions between hypothetical proteins with strong preferences for one or the other state that are bound to well-separated sites on the same DNA. A scenario is proposed for the activation of the ilvPG promoter on a supercoiled DNA by integration host factor.

Excitation and conduction in the majority of excitable cells, as originally described in the squid axon, are initiated by a transient and highly selective increase of the membrane Na conductance, which allows this ion to move passively down its electrochemical gradient (Hodgkin & Katz, 1949; Hodgkin & Huxley, 1952). The term ‘Na channel’ was introduced to describe the mechanism involved in this conductance change (Hodgkin & Keynes, 1955).