Theoretical conformational analysis of oxytocin molecule.

The total semi-empirical conformational analysis of the oxytocin molecule has been carried out. It has been revealed the two main types of stable structures of cyclic moiety backbone and the great lability of the tail. The optimal spacing of cyclic moiety side chains has been found for every backbone structure. The calculation results are in good agreement with the data of physico-chemical investigations. Among the set of stable molecule structures reported in the present study are structures with beta-turn conformation of the cyclic moiety backbone and without closer spacing of the cyclic moiety and the tail, as well as structures with closely spaced N- and C-terminal parts which, however, lack beta-turn in the cyclic moiety.     

The distribution of structures in evolving protein populations

Proteins exhibit a nonuniform distribution of structures. A number of models have been advanced to explain this observation by considering the distribution of designabilities, that is, the fraction of all sequences that could successfully fold into any particular structure. It has been postulated that more designable structures should be more common, although the exact nature of this relationship has not been addressed. We find that the nonuniform distribution of protein structures found in nature can be explained by the interplay of evolution and population dynamics with the designability distribution. The relative frequency of different structures has a greater-than-linear dependence on designability, making the distribution of observed protein structures more uneven than the distribution of designabilities. The distribution of structures is also affected by additional factors such as the topology of the sequence space and the similarity of other structures.     

Triple helical stabilities of guest-host collagen mimetic structures

The peptoid Nleu (N-isobutylglycine) has been successfully incorporated into a series of collagen mimetics composed of Gly-Pro-Nleu and Gly-Nleu-Pro sequences and has been able to maintain triple helices in appropriate structures. The achiral trimeric sequence Gly-Nleu-Nleu as a guest sequence in structures such as Ac-(Gly-Pro-Hyp)3-(Gly-Nleu-Nleu)3-(Gly-Pro-Hyp)3-NH2 retains triple helicity. As an extension of this study, we report, in this paper, on a series of guest-host collagen mimetic structures in which Gly-Nleu-Pro sequences are employed as the host. The guest sequences for these guest-host structures include Gly-Nleu-Nleu and Gly-Nx-Pro sequences where Nx is composed of a variety of alkyl and aralkyl peptoid residues. From these guest-host collagen mimetic structures, we are able to elucidate the contributions of hydrophobic and steric effects on triple helix formation. The Gly-Nleu-Pro sequences have been shown to be effective in inducing triple helicity. Conformational characterization of the guest-host collagen mimetic structures was established by techniques such as temperature-dependent optical rotation measurements and circular dichroism (CD) spectroscopy.     

A global resource for computational chemistry

A modular distributable system has been built for high-throughput computation of molecular structures and properties. It has been used to process 250,000 compounds from the NCI database and to make the results searchable by structures and properties. The IUPAC/NIST InChI specification and algorithm has been used to index the structures and enforce integrity during computation. A number of novel features of the PM5 Hamiltonian were identified as a result of the high-throughput approach. The system and the data can be redistributed and reused and promote the value of computed data as a primary chemical resource.     

Structures of Src-family tyrosine kinases

The crystal structures of three Src-family tyrosine kinases have been determined recently. The structure of the catalytic domain of Lck has been determined in the active autophosphorylated state. The structures of larger constructs of c-Src and Hck, containing the SH3, SH2 and catalytic domains, as well as a C-terminal regulatory tail, have been determined in the down-regulated state, phosphorylated in the C-terminal tail. A comparison of these structures leads to an unanticipated mechanism for the regulation of catalytic activity by cooperative interactions between the SH2, SH3 and catalytic domains.     

A study of the occurrence of regulator secondary structures in globular proteins

The distribution of regular secondary structures, viz. α-helices and β-strands, along the length of over 70 properties whose secondary structural details have been reported, has been analysed. The occurrence of these regular structures tends to be a maximum at the N- and C-termini. Our analysis suggests that both these free ends could possibly serve as nucleating centers for secondary structures and could play an important role in the folding of proteins.     

3dRNAscore: a distance and torsion angle dependent evaluation function of 3D RNA structures

Model evaluation is a necessary step for better prediction and design of 3D RNA structures. For proteins, this has been widely studied and the knowledge-based statistical potential has been proved to be one of effective ways to solve this problem. Currently, a few knowledge-based statistical potentials have also been proposed to evaluate predicted models of RNA tertiary structures. The benchmark tests showed that they can identify the native structures effectively but further improvements are needed to identify near-native structures and those with non-canonical base pairs. Here, we present a novel knowledge-based potential, 3dRNAscore, which combines distance-dependent and dihedral-dependent energies. The benchmarks on different testing datasets all show that 3dRNAscore are more efficient than existing evaluation methods in recognizing native state from a pool of near-native states of RNAs as well as in ranking near-native states of RNA models.     

The articular disc of the wrist. Limits and relations

The relationship between the discus articularis and its contiguous structures has been analyzed in 18 serially sectioned fetal hands. From this study, it can be concluded that these elements do not seem to be an extensive fibrous system emerging from the radius and reaching the metacarpal V, as it has been said, but a complex of clearly differentiated structures, of which further morphological details are given.     

Birefringence of Protein Solutions and Biological Systems. I

The quantitative interpretation of birefringence of biological structures such as muscle requires a knowledge of intrinsic birefringence of the components. The intrinsic birefringence of fibrous structures as determined by variation of solvent index is positive while the intrinsic birefringence of proteins in solution is negative as calculated by the Peterlin-Stuart theory. As a first step in clarifying this discrepancy the basis of the Peterlin-Stuart theory has been re-examined. The theory has been recalculated from the standpoint of light scattering and extended to particles whose length is not small compared to the wavelength. The birefringence of a system of particles possessing a shell with index different from the bulk solvent has been obtained in order to interpret measurements in mixed solvents.     

New approaches to the chemical synthesis of bioactive oligosaccharides.

The past year has seen some major advances in the area of carbohydrate synthesis using chemical methods. Progress in all areas of synthetic methodology, including new protecting groups and coupling methods, has been reported. A number of complex carbohydrate structures have been prepared using known, as well as new, methods. The goal to allow nonspecialists access to defined carbohydrate structures for biochemical, biophysical and biological studies has drawn closer by the introduction of two approaches towards synthesis automation. A one-pot glycosylation strategy utilized computer-assisted synthesis planning and the first solid-phase automated synthesizer was introduced very recently.     

Modeling of steady-state and relaxation elastic properties of the papillary muscle at rest

The biomechanical modeling of a papillary muscle preparation as an adequate object for studying the properties of the myocardial tissue under uniaxial stretching has been performed. The steady-state and relaxation tests of the papillary muscle of laboratory animals (rabbit and rat) have been conducted in normal conditions and after the maceration of intracellular structures with high ionic strength solution. It has been shown that the main contribution to the viscoelastic properties in the initial range of physiological deformations is made by the connective tissue skeleton, whereas under large physiological deformations, by intracellular structures.     

Inverted repeats in the DNA of plasmid pCU1

Renaturable regions in the DNA strands of the N group plasmid pCU1 have been visualized as stem-loop structures by electron microscopy. Four such distinct structures are described, the smallest of which is within the loop of a larger one. The region of pCU1 in which these structures occur has several restriction sites. This and the availability of plasmid deletions and recombinants has permitted the mapping of these structures relative to one another and to the restriction and functional map of the plasmid. The replication and maintenance region of the plasmid is located within one of these stem-loop structures.     

The emergence of scaling in sequence-based physical models of protein evolution

It has recently been discovered that many biological systems, when represented as graphs, exhibit a scale-free topology. One such system is the set of structural relationships among protein domains. The scale-free nature of this and other systems has previously been explained using network growth models that, although motivated by biological processes, do not explicitly consider the underlying physics or biology. In this work we explore a sequence-based model for the evolution protein structures and demonstrate that this model is able to recapitulate the scale-free nature observed in graphs of real protein structures. We find that this model also reproduces other statistical feature of the protein domain graph. This represents, to our knowledge, the first such microscopic, physics-based evolutionary model for a scale-free network of biological importance and as such has strong implications for our understanding of the evolution of protein structures and of other biological networks.     

Infrared spectra of the Gramicidin A transmembrane channel: the single-stranded-beta 6-helix

IR spectra are reported for preparations of Gramicidin A and malonyl Gramicidin A incorporated as the channel state in phospholipid structures. In this preparation Gramicidin A has already been shown to be unequivocally in the single-stranded beta-helical conformation. The result is an amide I frequency of 1633 +/- 1 cm-1. This demonstrates that the single-stranded beta-helix has an amide I frequency that has previously been considered to be diagnostic of antiparallel double-stranded beta-helix and of beta-sheet structures.     

Rheological properties of ovalbumin hydrogels as affected by surfactants addition

The gel properties of ovalbumin mixtures with three different surfactants (sodium perfluorooctanoate, sodium octanoate and sodium dodecanoate) have been studied by rheological techniques. The gel elasticities were determined as a function of surfactant concentration and surfactant type. The fractal dimension of the formed structures was evaluated from plots of storage modulus against surfactant concentration. The role of electrostatic, hydrophobic and disulfide SS interactions in these systems has been demonstrated to be the predominant. The viscosity of these structures tends to increase with surfactant concentration, except for the fluorinated one. Unfolded ovalbumin molecules tend to form fibrillar structures that tend to increase with surfactant concentration, except for the fluorinated one. This fact has been related to the particular nature of this molecule.     

WAXS studies of the structural diversity of hemoglobin in solution

Specific ligation states of hemoglobin are, when crystallized, capable of taking on multiple quaternary structures. The relationship between these structures, captured in crystal lattices, and hemoglobin structure in solution remains uncertain. Wide-angle X-ray solution scattering (WAXS) is a sensitive probe of protein structure in solution that can distinguish among similar structures and has the potential to contribute to these issues. We used WAXS to assess the relationships among the structures of human and bovine hemoglobins in different liganded forms in solution. WAXS data readily distinguished among the various forms of hemoglobins. WAXS patterns confirm some of the relationships among hemoglobin structures that have been defined through crystallography and NMR and extend others. For instance, methemoglobin A in solution is, as expected, nearly indistinguishable from HbCO A. Interestingly, for bovine hemoglobin, the differences between deoxy-Hb, methemoglobin and HbCO are smaller than the corresponding differences in human hemoglobin. WAXS data were also used to assess the spatial extent of structural fluctuations of various hemoglobins in solution. Dynamics has been implicated in allosteric control of hemoglobin, and increased dynamics has been associated with lowered oxygen affinity. Consistent with that notion, WAXS patterns indicate that deoxy-Hb A exhibits substantially larger structural fluctuations than HbCO A. Comparisons between the observed WAXS patterns and those predicted on the basis of atomic coordinate sets suggest that the structures of Hb in different liganded forms exhibit clear differences from known crystal structures.     

A comprehensive analysis of the Greek key motifs in protein beta-barrels and beta-sandwiches

The Greek key motifs are the topological signature of many beta-barrels and a majority of beta-sandwich structures. An updated survey of these structures integrates many early observations and newly emerging patterns and provides a better understanding of the unique role of Greek keys in protein structures. A stereotypical Greek key beta-barrel accommodates five or six strands and can have 12 possible topologies. All except one six-stranded topologies have been observed, and only one five-stranded topologies have been seen in actual structures. Of the representative beta-barrel structures analyzed here, half have left-handed Greek keys. This result challenges the empirical claim of the handedness regularity of Greek keys in beta-barrels. One of the five-stranded topologies that has not been observed in beta-barrels comprises two overlapping Greek keys. The two three-dimensional forms of this topology constitute a structural unit that is present in a vast majority of known beta-sandwich structures. Using this unit as the root, we have built a new taxonomy tree for the beta-sandwich folds and deduced a set of rules that appear to constrain how other beta-strands adjoin the unit to form a larger double-layered structure. These rules, though derived from a larger data set, are essentially the same as those drawn from earlier studies, suggesting that they may reflect the true topological constraints in the design of beta-sandwich structures. Finally, a novel variant of the Greek key motif (defined here as the twisted Greek key) has emerged which introduces loop crossings into the folded structures. Proteins 2000;40:409-419.     

On the purported presence of fossilized collagen fibres in an ichthyosaur and a theropod dinosaur

Since the discovery of exceptionally preserved theropod dinosaurs with soft tissues in China in the 1990s, there has been much debate about the nature of filamentous structures observed in some specimens. Sinosauropteryx was the first non‐avian theropod to be described with these structures, and remains one of the most studied examples. Despite a general consensus that the structures represent feathers or feather homologues, a few identify them as degraded collagen fibres derived from the skin. This latter view has been based on observations of low‐quality images of Sinosauropteryx, as well as the suggestion that because superficially similar structures are seen in Jurassic ichthyosaurs they cannot represent feathers. Here, we highlight issues with the evidence put forward in support of this view, showing that integumentary structures have been misinterpreted based on sedimentary features and preparation marks, and that these errors have led to incorrect conclusions being drawn about the existence of collagen in Sinosauropteryx and the ichthyosaur Stenopterygius. We find that there is no evidence to support the idea that the integumentary structures seen in the two taxa are collagen fibres, and confirm that the most parsimonious interpretation of fossilized structures that look like feather homologues in Sinosauropteryx is that they are indeed the remains of feather homologues.     

Discovery of novel intracellular receptor modulating drugs

Utilizing the co-transfection assay as a guide to determining structure activity relationships, we have been pursuing the discovery of non-steroidal hPR modulators. Small molecule, non-steroidal lead structures have been identified. Optimization of these structures has yielded more potent hPR modulators. Improved cross-reactivity profiles with other intracellular receptors are a feature of these compounds owing to their non-steroidal nature.