An attempt is made to establish the historical context in which the structure and function of haemoglobin were investigated by X-ray crystallographers in the 1940s and 50s. It is concluded that until the 1960s the interpretations of the data of crystallographic investigations were dependent upon the results of applying traditional techniques of physical and organic chemistry. In the case of haemoglobin, no less than in those of smaller organic molecules, crystallographic studies in the 1940s and early 50s served to (...) validate, and metricize conclusions already suggested or adopted on other grounds, but the subsequent tracing of the actual conformation of the polypeptide chains in the globin portion of the molecule was a unique achievement of the X-ray crystallographers and marked the beginning of the independent establishment of structures by this profession. The impact of this achievement upon the structure-function relationships of haemoglobin is discussed briefly. (shrink)

ABSTRACT It has long been held that the structure of a protein is determined solely by the interactions of the atoms in the sequence of amino acids of which it is composed, and thus the stable, biologically functional conformation should be predictable by ab initio or de novo methods. However, except for small proteins, ab initio predictions have not been successful. We explain why this is the case and argue that the relationship among the different methods, models, and representations of (...) protein structure is one of integrative pluralism. Our defence appeals to specific features of the complexity of the functional protein structure and to the partial character of representation in general. We present examples of integrative strategies in protein science. _1._ Introduction _2._ Partiality of Representation _3._ Protein Functional Complexity _4._ Modelling Protein Structure _4.1_ Integrating ab initio and experimental models _4.2_ Integrating multiple experimental models _5._ Conclusion. (shrink)

Scientific models share one central characteristic with fiction: their relation to the physical world is ambiguous. It is often unclear whether an element in a model represents something in the world or presents an artifact of model building. Fiction, too, can resemble our world to varying degrees. However, we assign a different epistemic function to scientific representations. As artifacts of human activity, how are scientific representations allowing us to make inferences about real phenomena? In reply to this concern, philosophers of (...) science have started analyzing scientific representations in terms of fictionalization strategies. Many arguments center on a dyadic relation between the model and its target system, focusing on structural resemblances and “as if” scenarios. This chapter provides a different approach. It looks more closely at model building to analyze the interpretative strategies dealing with the representational limits of models. How do we interpret ambiguous elements in models? Moreover, how do we determine the validity of model-based inferences to information that is not an explicit part of a representational structure? I argue that the problem of ambiguous inference emerges from two features of representations, namely their hybridity and incompleteness. To distinguish between fictional and non-fictional elements in scientific models my suggestion is to look at the integrative strategies that link a particular model to other methods in an ongoing research context. To exemplify this idea, I examine protein modeling through X-ray crystallography as a pivotal method in biochemistry. (shrink)

It has long been held that the structure of a protein is determined solely by the interactions of the atoms in the sequence of amino acids of which it is composed, and thus the stable, biologically functional conformation should be predictable by ab initio or de novo methods. However, except for small proteins, ab initio predictions have not been successful. We explain why this is the case and argue that the relationship among the different methods, models, and representations of protein (...) structure is one of integrative pluralism. Our defence appeals to specific features of the complexity of the functional protein structure and to the partial character of representation in general. We present examples of integrative strategies in protein science. 1. Introduction2. Partiality of Representation3. Protein Functional Complexity4. Modelling Protein Structure4.1 Integrating ab initio and experimental models4.2 Integrating multiple experimental models5. Conclusion. (shrink)

As early as 1981, about 1 year before Shechtman’s discovery of an actual quasicrystal, Alan L. Mackay discussed, in a seminal paper, the first steps for the expansion of crystallography toward its modern phase. In this phase, new possibilities of structures and order, such as the structures of five-fold symmetry, for crystals have been discovered. Medieval Islamic decorators as well as Albrecht Dürer, Johannes Kepler, Roger Penrose, Mackay himself, and other pioneer crystallographers raised important contributions to the theoretical discovery (...) of crystalline possibilities long before or independently of the discovery of their actual existence. In this paper, I discuss further the philosophical significance of Mackay’s theoretical discovery and his contribution to the expansion of pure geometrical crystallography, biological crystallography, and generalized crystallography. (shrink)

“I myself was forced to call myself a molecular biologist because when inquiring clergymen asked me what I did, I got tired of explaining that I was a mixture of crystallographer, biophysicist, biochemist, and geneticist.” Thus explained Francis Crick, who with James Watson discovered in 1953 the double helical structure of DNA, the genetic material..

The formation of particles of elemental tin in association with the nucleation of the precipitate phase θ′ in an Al–1.7 at.% Cu–0.01 at.% Sn alloy has been investigated by high resolution transmission electron microscopy. Analysis of lattice images has demonstrated that these tin particles associated with θ′ platelets formed during short-term ageing (typically 3 min at 200 degrees Celcius) exhibit a crystallographic form that is distinctly different from that previously reported in such ternary alloys and also from that observed in (...) the binary alloy Al–0.01 at.% Sn. Those tin particles that could be clearly identified as β-Sn phase shared a crystallographic relationship of the form (001)Sn‖(001)Al‖(001)θ′, [110]Sn‖[100]Al‖[100]θ′ with the α-Al and θ′ phases with which they were simultaneously in contact. The observations imply that, while tin may assist nucleation of platelets of θ′, the formation of θ′ equally influences the crystallography of β--Sn that forms in association with θ′. Following prolonged ageing (typically 50 h at 200°C), the β-Sn particles in contact with θ′ plates had coarsened and diminished in number, and most now exhibited an orientation relationship with α-Al matrix similar to that observed in the binary alloy Al–0.01 at.% Sn (i.e. (100)Sn‖(111)Al, [010]Sn‖[112]Al) and to that previously observed in the later stages of ageing of the ternary alloy Al–1.7 at.% Cu–0.01 at.% Sn. (shrink)

Allosteric and transmembrane signaling are among the major questions of structural biology. Here, we review and discuss signal transduction in four-helical TM bundles, focusing on histidine kinases and chemoreceptors found in two-component systems. Previously, piston, scissors, and helical rotation have been proposed as the mechanisms of TM signaling. We discuss theoretically possible conformational changes and examine the available experimental data, including the recent crystallographic structures of nitrate/nitrite sensor histidine kinase NarQ and phototaxis system NpSRII:NpHtrII. We show that TM helices can (...) flex at multiple points and argue that the various conformational changes are not mutually exclusive, and often are observed concomitantly, throughout the TM domain or in its part. The piston and scissoring motions are the most prominent motions in the structures, but more research is needed for definitive conclusions. Models of allosteric transmembrane signaling in microbial sensor histidine kinases and chemoreceptors are discussed in light of recent crystallographic structures. It is shown that the TM α-helices are flexible and various conformational changes are often observed concomitantly. The piston and scissoring motions are the most prominent in the structures. (shrink)

Together with microtubules and actin microfilaments, ∼11 nm wide intermediate filaments (IFs) constitute the integrated, dynamic filament network present in the cytoplasm of metazoan cells. This network is critically involved in division, motility and other cellular processes. While the structures of microtubules and microfilaments are known in atomic detail, IF architecture is presently much less understood. The elementary ‘building block’ of IFs is a highly elongated, rod‐like dimer based on an α‐helical coiled‐coil structure. Assembly of cytoplasmic IF proteins, such as (...) vimentin, begins with a lateral association of dimers into tetramers and gradually into the so‐called unit‐length filaments (ULFs). Subsequently ULFs start to anneal longitudinally, ultimately yielding mature IFs after a compaction step. For nuclear lamins, however, assembly starts with a head‐to‐tail association of dimers. Recently, X‐ray crystallographic data were obtained for several fragments of the vimentin dimer. Based on the dimer structure, molecular models of the tetramer and the entire filament are now a possibility. BioEssays 25:243–251, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

Ets proteins are a family of transcription factors that regulate the expression of a myriad of genes in a variety of tissues and cell types. This functional versatility emerges from their interactions with other structurally unrelated transcription factors. Indeed, combinatorial control is a characteristic property of Ets family members, involving interactions between Ets and other key transcriptional factors such as AP1, SRF, and Pax family members. Intriguingly, recent molecular modeling and crystallographic data suggest that not only the ETS DNA-binding domain, (...) but also the DNA recognition helix α3, are often directly required for Ets partner's selection. Indeed, while most DNA-binding proteins appear to exploit differences within their DNA recognition helices for sites selection, the Ets proteins exploit differences in their surfaces that interact with other transcription factors, which in turn may modify their DNA-binding properties in a promoter-specific fashion. Taken together, the gene-specific architecture of these unique complexes can mediate the selective control of transcriptional activity. BioEssays 24:362–370, 2002. ©2002 Wiley Periodicals, Inc. (shrink)

Unraveling the molecular detail of insulin receptor activation has proved challenging, but a major advance is the recent determination of crystallographic structures of insulin in complex with its primary binding site on the receptor. The current model for insulin receptor activation is that two distinct surfaces of insulin monomer engage sequentially with two distinct binding sites on the extracellular surface of the insulin receptor, which is itself a disulfide‐linked (αβ)2 homodimer. In the process, conformational changes occur both within the hormone (...) and the receptor, the latter resulting in the disruption of the intracellular interactions that hold the kinase domains in their basal state and in the initiation of the phosphorylation events that drive insulin signaling. The purpose of this paper is to summarize the extant structural data relating to hormone binding and how it effects receptor activation, as well as to discuss the issues that remain unresolved. (shrink)

The nm23 gene, a putative metastasis suppressor gene, was originally identified by its reduced expression in highly metastatic K‐1735 murine melanoma cell lines, as compared to related, low metastatic melanoma cell lines. Transfection of nm23 cDNA has been reported to suppress malignant progression in Drosophila and mammalian cells. Highly conserved homologues of nm23 have been found in organisms ranging from the prokaryote Myxococcus xanthus to Drosophila, where the gene is involved in normal development and differentiation. The product of the nm23 (...) gene exhibits a nucleoside diphosphate kinase activity, yet the nucleoside diphosphate kinase activity of Nm23 does not correlate with its apparent biological functions. We review recent cellular, genetic, biochemical and X‐ray crystallographic data to formulate and evaluate hypotheses concerning the molecular mechanism of nm23 action. (shrink)

SummaryWilliam Barlow was an important if unconventional scientist, known for having developed the ‘closest-packing’ atomic models of crystal structure. He resumed an early nineteenth-century tradition of utilizing crystallographical and chemical data to determine atomic arrangements in crystals. This essay recounts Barlow's career and scientific activity in three parts: His place in the tradition of determining atomic arrangement in context of this earlier tradition and of contemporaneous developments of crystallography and chemistry, his unconventional career, and the ‘success’ of his program to (...) determine atomic arrangements in crystals and its influence on the work of William Lawrence Bragg. (shrink)

The lodestone is an extremely rare form of the mineral magnetite that occurs naturally as a permanent magnet. It therefore attracts metallic iron as well as fragments of ordinary ‘inert’ magnetite. This ‘magic’ property was known to many ancient cultures, and a powerful lodestone has always commanded a high price. By the eleventh century AD the Chinese had discovered that a freely suspended elongated lodestone would tend to set with its long axis approximately north–south, and utilized this property in the (...) magnetic compass. They also appear to have discovered that this invaluable characteristic could be handed‐on to a steel needle if the latter were contacted with, or stroked by, a lodestone.The magnetism of the lodestone was scientifically investigated by William Gilbert in the sixteenth century, when he defined its ‘poles' and the well‐known rule that ‘like poles repel, unlike attract’. He also studied ‘inclination’ and ‘variation’, and means to aid the preservation of magnetic power. How to concentrate it by ‘arming’ the lodestone with caps or pole‐pieces of soft iron was discovered in the same century. These methods have been repeated, confirmed, and improved. The lodestone occupies a vital place in the history of magnetism, but little beyond Gilbert's work can be reached by historical studies because vastly improved steel or alloy permanent magnets, and electromagnets, replaced it before quantitative measurements were developed. These techniques have therefore been applied retrospectively to both museum specimens and contemporary natural lodestones. A good source of the latter was found to be the igneous complex known as Magnet Cove, Arkansas, and this material has been used as the ‘type example’. All specimens were discrete, well‐rounded, rusty brown pebbles found near the surface. Their unweathered interiors were black titanomagnetite. No significant trace element or crystallographic differences could be found between the lodestones and the magnetically inert material that always accompanied them. The magnetic moment per unit volume of the ‘as‐found’ Magnet Cove lodestones varied between 6.5 and 11.6 emu cm−3, which compares poorly with the hundreds of units characteritzing modern permanent magnets. Hysteresis loops gave a saturation intensity of 27–51 emu cm−3, suggesting that intensity has diminished since formation. This agrees with general experience of magnets, especially in the absence of a ‘keeper’. The initial volume susceptibility of Magnet Cove magnetite was about 0.18 for low fields, and always remained <1. This means that a normal terrestrial magnetic field with a maximum vector <1 Oe is unable to induce even the low magnetic moments we see today, while a field approaching 1000 Oe is required for saturation. These parameters, and the rare occurrence of lodestones as near‐surface fragments, support suggestions that they are the product of a lightning strike upon an exposure of a suitable magnetite. Transient currents averaging 30 000 A have been measured. This would give rise to a zone of potential magnetic saturation at least 12 cm in diameter, to which some of the ejected fragments would be exposed. An attempt to determine the period elapsed since formation of the Magnet Cove lodestone was made by annealing magnetically saturated specimens at temperatures up to 500°C, and measuring J v at weekly intervals for 100 days. The decay curves visually resembled exponential functions, but mathematical tests proved that they were not strictly so. Interpretation was therefore difficult, but a pragmatic procedure involving excessive extrapolation suggested an ‘age’ of about 3500 years. (shrink)

In the present work we explore the effects that an H impurity produces upon the geometry and electronic structure of the CaTiO 3 crystal considering the cubic and orthorhombic crystallographic lattices of the material. A quantum-chemical method based on the Hartree-Fock formalism and the periodic large-unit-cell model is used throughout the work. The analysis of the results shows that the interstitial H impurity binds to one of the O atoms forming the so-called O-H group. At equilibrium, the O-H distances are (...) found to be equal to 0.89 and 1.04 Å for cubic and orthorhombic lattices respectively. Atomic displacements and relaxation energies are analysed comparing the obtained results in the cubic lattice with those in the orthorhombic lattice. In the cubic phase the computed relaxation energy of vicinity of the O-H group is found to be equal to 1.1 eV and the atomic displacements generally obey the Coulomb law. So, the negatively charged O atoms move outwards from the defective region by about 0.09 Å while the positively charged Ti and Ca atoms move towards the defective region by about 0.05 and 0.01 Å respectively. A similar effect is observed in the orthorhombic lattice of CaTiO 3 doped with an H atom. It is necessary to mention that different O positions in the orthorhombic structure are considered for the O-H bond creation. The computed relaxation energies of the atomic displacements in this structure are found to be equal to 2.3 and 2.1 eV depending on the crystallographic type of the bonding O atom. (shrink)

The Medical Research Council Laboratory of Molecular Biology (formerly the Medical Research Council Unit for the Study of Molecular Structure of Biological Systems) in Cambridge (England) played a key role in the postwar history of molecular biology. The paper, focussing on the early history of the institution, aims to show that the creation of the laboratory and the making of molecular biology were part of a new scientific culture set in place after World War II. In five interlinked parts it (...) deals with the institutional creation of the MRC unit dedicated to the crystallographic analysis of biological molecules; the attraction of postwar biophysics, the heading under which the work of the unit initially fell; the people who joined the laboratory and their appropriation of new technologies, in particular the electronic computer for protein crystal structure determination; the cultural appeal of postwar crystallography, as exemplified in the use of crystal structure diagrams for a wide series of consumer goods at the Festival of Britain in 1951 and the display of molecular models at the Brussels World's Fair in 1958, a key site for the presentation of science and its role in the postwar world. (shrink)

The Medical Research Council Laboratory of Molecular Biology in Cambridge played a key role in the postwar history of molecular biology. The paper, focussing on the early history of the institution, aims to show that the creation of the laboratory and the making of molecular biology were part of a new scientific culture set in place after World War II. In five interlinked parts it deals with the institutional creation of the MRC unit dedicated to the crystallographic analysis of biological (...) molecules; the attraction of postwar biophysics, the heading under which the work of the unit initially fell; the people who joined the laboratory and their appropriation of new technologies, in particular the electronic computer for protein crystal structure determination; the cultural appeal of postwar crystallography, as exemplified in the use of crystal structure diagrams for a wide series of consumer goods at the Festival of Britain in 1951 and the display of molecular models at the Brussels World’s Fair in 1958, a key site for the presentation of science and its role in the postwar world. (shrink)

Inspiring and empowering, this journey behind the scenes of humanity's greatest creations reveals the surprising way we make something new. What do Thomas Jefferson's ice cream recipe, Coca Cola, and Chanel No. 5 have in common? They all depended on a nineteenth-century African boy who, with a single pinch, solved one of nature's great riddles and gave birth to the multimillion-dollar vanilla industry. Kevin Ashton opens his book with the fascinating story of the young slave who launched a flavor revolution (...) to show that invention and creation come in unexpected shapes and sizes. From the crystallographer's laboratory where the secrets of DNA were first revealed by a long-forgotten woman, to the electromagnetic chamber where the stealth bomber was born on a 25-cent bet, Ashton weaves tales of humanity's greatest creations to unpack the surprising true process of discovery. Drawing on the Amish and the iPhone, Kandinsky and cans of Coke, Lockheed, South Park, and the Wright brothers--who set out to "fly a horse"--he showcases the seemingly unremarkable individuals, gradual steps, multiple failures, and countless ordinary--and usually uncredited--acts that led to our most astounding breakthroughs. Creators, he shows, apply everyday, ordinary thinking that we are all capable of in particular ways, taking thousands of small steps, working in an endless loop of problem and solution. He explores why innovators meet resistance and how they overcome it, why most organizations stifle creative people, and how the most creative organizations work. In a passionate and profound narrative that amazes and inspires, Ashton's book sheds new light on how "new" comes to be. (shrink)