Average values of a dissimilarity measure not requiring sequence alignment are twice the averages of conventional mismatch counts requiring sequence alignment for a variety of computer-generated model systems

Summary A measure of sequence similarity,d _t, not requiring prior sequence alignment gave correct results for a variety of computer-generated model sequences without and with gaps for all degrees of substitution,s. Measured was the squared Euclidean distance between vectors of counts of t-tuplets of characters in the two sequences. In models without gaps and without Needleman-Wunsch alignment, averaged was very closely equal to twice average conventional mismatch counts,m. In these models one of each of the conditions on the Jukes-Cantor model was violated in turn: (1) both descendant lineages receive the same number of substitutions, (2) all sites are equally likely to be substituted, (3) all different replacement characters are equally likely to be chosen, and (4) all original characters are equally likely to be substituted. In Jukes-Cantor models with gaps Needleman-Wunsch alignment was necessarily performed, a procedure that generally produced incorrect values ofm. For these models averaged was found to be very closely equal to twice the averagem estimated from the known value ofs using the inverted Jukes-Cantor formula.     

Effect of Cosmological Neutrinos on Discrimination Between the Two Enantiomers of a Chiral Molecule

In the framework of an extraterrestrial origin of biological homochirality, universal mechanisms are of particular interest. In this sense we consider the weak parity-violating neutrino-electron interaction through weak charged currents W ^± between the relic flux of cosmological neutrinos and the electrons of a chiral molecule. We use the known theoretical result of the split in energy of the two helicity sates of an electron in the cosmic neutrino bath, due to weak charged currents. In the case that electrons of a chiral molecule are submitted to a helicoidal potential due to the nuclear conformation, these electrons have opposite helicities for the two enantiomers of the molecule and consequently the mentioned neutrino-electron interaction would produce a splitting in energy between the two enantiomers. An estimation of this energy for the case of a single electron yields a small value of the order of 10⁻²⁶ eV. This value results amplified by the contribution of all the molecular electrons having helicity and other possible mechanisms.     

Quantitative structure activity relationships of some pyridine derivatives as corrosion inhibitors of steel in acidic medium

Quantum chemical calculations using the density functional theory (B3LYP/6-31G* DFT) and semi-empirical AM1 methods were performed on ten pyridine derivatives used as corrosion inhibitors for mild steel in acidic medium to determine the relationship between molecular structure and their inhibition efficiencies. Quantum chemical parameters such as total negative charge (TNC) on the molecule, energy of highest occupied molecular orbital (E _HOMO), energy of lowest unoccupied molecular orbital (E _LUMO) and dipole moment (μ) as well as linear solvation energy terms, molecular volume (Vi) and dipolar-polarization (π*) were correlated to corrosion inhibition efficiency of ten pyridine derivatives. A possible correlation between corrosion inhibition efficiencies and structural properties was searched to reduce the number of compounds to be selected for testing from a library of compounds. It was found that theoretical data support the experimental results. The results were used to predict the corrosion inhibition of 24 related pyridine derivatives.     

Fluorescence spectroscopic analysis on interaction of fleroxacin with pepsin

The interaction between fleroxacin (FLX) and pepsin was investigated by spectrofluorimetry. The effects of FLX on pepsin showed that the microenvironment of tryptophan residues and molecular conformation of pepsin were changed based on fluorescence quenching and synchronous fluorescence spectroscopy in combination with three‐dimensional fluorescence spectroscopy. Static quenching was suggested and it was proved that the fluorescence quenching of pepsin by FLX was related to the formation of a new complex and a non‐radiation energy transfer. The quenching constants K_SV, binding constants K and binding sites n were calculated at different temperatures. The molecular interaction distance (r = 6.71) and energy transfer efficiency (E = 0.216) between pepsin and FLX were obtained according to the Forster mechanism of non‐radiation energy transfer. Hydrophobic and electrostatic interaction played a major role in FLX–pepsin association. In addition, the hydrophobic interaction and binding free energy were further tested by molecular modeling study. Copyright © 2013 John Wiley & Sons, Ltd.     

Ribonucleotide reductase inhibition by p-alkoxyphenols studied by molecular docking and molecular dynamics simulations

Ribonucleotide reductase (RNR) is necessary for production of the precursor deoxyribonucleotides for DNA synthesis. Class Ia RNR functions via a stable free radical in one of the two components protein R2. The enzyme mechanism involves long range (proton coupled) electron transfer between protein R1 and the tyrosyl radical in protein R2. Earlier experimental studies showed that p-alkoxyphenols inhibit RNR. Here, molecular docking and molecular dynamics simulations involving protein R2 suggest an inhibition mechanism for p-alkoxyphenols . A low energy binding pocket is identified in protein R2. The preferred configuration provides a structural basis explaining their specific binding to the Escherichia coli and mouse R2 proteins. Trp48 (E. coli numbering), on the electron transfer pathway, is involved in the interactions with the inhibitors. The relative order of the binding energies calculated for the phenol derivatives to protein R2 is correlated with earlier experimental data on inhibition efficiency, in turn related to increasing size of the hydrophobic alkyl substituents. Using the configuration identified by molecular docking as a starting point for molecular dynamics simulations, we find that the p-allyloxyphenol interrupts the catalytic electron transfer pathway of the R2 protein by forming hydrogen bonds with Trp48 and Asp237, thus explaining the inhibitory activity of p-alkoxyphenols.     

Insight into a molecular interaction force supporting peptide backbones and its implication to protein loops and folding

Although not being classified as the most fundamental protein structural elements like α-helices and β-strands, the loop segment may play considerable roles for protein stability, flexibility, and dynamic activity. Meanwhile, the protein loop is also quite elusive; i.e. its interactions with the other parts of protein as well as its own shape-maintaining forces have still remained as a puzzle or at least not quite clear yet. Here, we report a molecular force, the so-called polar hydrogen–π interaction (Hp–π), which may play an important role in supporting the backbones of protein loops. By conducting the potential energy surface scanning calculations on the quasi π-plane of peptide bond unit, we have observed the following intriguing phenomena: (1) when the polar hydrogen atom of a peptide unit is perpendicularly pointing to the π-plane of other peptide bond units, a remarkable Hp–π interaction occurs; (2) the interaction is distance and orientation dependent, acting in a broad space, and belonging to the ‘point-to-plane’ one. The molecular force reported here may provide useful interaction concepts and insights into better understanding the loop’s unique stability and flexibility feature, as well as the driving force of the protein global folding.     

Pharmacophore mapping,molecular docking and QSAR studies of structurally diverse compounds as CYP2B6 inhibitors

Pharmacophore mapping, molecular docking and quantitative structure–activity relationship (QSAR) studies were carried out for a structurally diverse set of 48 compounds as CYP2B6 inhibitors. The generated best pharmacophore hypotheses from the three methods of conformer generation (FAST, BEST and conformer algorithm based on energy screening and recursive buildup) indicate the importance of two features, namely, hydrogen bond acceptor [electron-rich centre] and ring aromaticity. The distance between the two centres of the important features for ideal inhibitors varied from 5.82 to 6.03 Å. The chemometric tools used for the QSAR analysis were genetic function approximation (GFA) and genetic partial least squares. The developed QSAR models indicate the importance of an electron-rich centre, size of molecule, impact of branching and ring system and distribution of charges in the molecular surface. The docking study confirms the importance of an electron-rich centre for binding with the iron atom of the cytochrome enzyme. A GFA model with spline option was found to be the best model based on internal validation as well as the r ² _{m (overall)} criterion (Q ² = 0.772, r ² _{m (overall)} = 0.774). According to the external prediction statistics (R ² _pred = 0.876), another GFA-derived model with spline option outperforms the remaining models.     

An Occam’s razor approach to chemical hardness: <Emphasis Type="Italic">lex parsimoniae</Emphasis>

The term “chemical hardness” refers to the resistance to deformation of the electronic density of a system; the greater this resistance, the “harder” the system. Polarizability, a physical property, is an inverse measure of resistance to deformation and thus should be inversely related to hardness. This is indeed generally accepted. Hardness has been postulated to be the second derivative of a system’s energy with respect to its number of electrons, despite the fact that this involves the differentiation of a noncontinuous function. This second derivative is typically approximated as the difference between the ionization energy I and the electron affinity A of the ground-state system, which results in ambiguity in that many molecules do not form stable negative ions. For atoms, the quantity I ? A does vary approximately inversely with polarizability, but this is only because the electron affinity is usually relatively low and ionization energy is known to be inversely related to polarizability for atoms. However, molecular polarizability depends primarily upon volume, and so does not show an acceptable inverse correlation with I ? A. Since both hardness and polarizability refer to the same property of a system—its resistance to deformation of the electronic density, we propose that the reciprocal of polarizability be taken to be a measure of hardness. We show that polarizabilities that are not known can be estimated quite accurately in terms of the average local ionization energies on the atomic or molecular surfaces and, for molecules, their volumes.     

Presynaptic chromosome behavior in Lilium

The orientation and movement of chromosomes throughout premeiotic interphase in Lilium speciosum has been studied through three-dimensional reconstruction of electron micrographs of serial thin sections through microsporocyte nuclei. Anthers were chosen based upon the correlation between their length and the stage of the microsporocytes within, and were fixed for light and electron microscopy. A light microscopic survey of both squash preparations and thick sections was done to select the material for electron microscopic analysis. Microsporocytes from the selected anthers were serially sectioned (200–300 consecutive gold sections), stained for electron microscopy, and alternate sections of entire nuclei were photographed. Prints were traced, and these tracings were compiled to produce a composite of each nucleus in which the locations of the centromeres were indicated. The position of the centromeric structures (CeS) in each nucleus was characterized by the average distance between CeSs, the average distance between CeSs and the nuclear envelope, and the coefficients of variation of these distances. A test was made to determine if CeSs were positioned evenly throughout the nucleus. — The results indicate that centromeres do not exhibit extensive movement during PMI in Lilium speciosum cv. Rosemede and that homologous chromosomes do not undergo a prealignment during PMI which facilitates their pairing during later meiotic stages. A model of centromere movement in the interphase nucleus is proposed.     

The solution structure of cytochrome c 6 from the green alga Monoraphidium braunii

 The three-dimensional structure in solution of the reduced form of cytochrome c ₆ from the green alga Monoraphidium braunii has been solved through NMR data. Cytochrome c ₆ acts as a small mono-heme electron carrier protein between the two membrane-embedded complexes cytochrome f and photosystem I. The structure was determined using 1278 relevant interproton NOEs out of 1776 assigned NOEs with distance geometry (DG) calculations which included 36 stereospecific assignments and 20 experimentally found angle constraints. The family of structures obtained from the DG calculations was subjected to energy minimization and molecular dynamics simulation using previously defined force field parameters for the heme and its ligands. In all stages of the calculations, the solution structure is well defined and similar to the now available X-ray structure. Received: 18 January 1996 / Accepted: 19 April 1996     

The ultrastructural study of the interphase cell nucleus of Lacandonia schismatica (Lacandoniaceae: Triuridales) reveals a non-typical extranucleolar particle

By light and electron microscope cytochemistry we characterized the interphase nucleus of Lacandonia schismatica, the only known species of the new plant family Lacandoniaceae, whose most peculiar feature is the inverted position of the sexual organs, an aspect never found before among flowering plants. Furthermore, we compare it to Triuris alata, a related species, to Voyria aphylla (a dicotyledon), to Gymnosiphon divaricatus (a monocotyledon) and also to saprophytes. The reticulated chromatin of L schismatica and T alata is similar to that of other monocotyledons. In addition, we describe a unique type of RNP granules in the interchromatin space which are about 32 ± 3 nm SD in diameter and occur as huge clusters. They are intermediate in size and spatial distribution between inter- and peri-chromatin granules. We term them ‘Lacandonia granules’. The granules were also found in T alata. They are 31 ± 2 nm in diameter. No significant differences in size were observed between them (P > 0.05). Synaptonemallike complexes and ring-shaped structures were seen in interphase nuclei of somatic cells of these species. Coiled and nucleolus-associated bodies, as well as centromeres were also found in these two organisms. On the contrary, Vaphylla and G divaricatus display a chromocentric nuclear organization. The nuclear similarities between L schismatica and T alata suggest extremely close phylogenetic relationships between them.     

A distance-type measure approach to the analysis of copy number variation in DNA sequencing data

Background

The next generation sequencing technology allows us to obtain a large amount of short DNA sequence (DNA-seq) reads at a genome-wide level. DNA-seq data have been increasingly collected during the recent years. Count-type data analysis is a widely used approach for DNA-seq data. However, the related data pre-processing is based on the moving window method, in which a window size need to be defined in order to obtain count-type data. Furthermore, useful information can be reduced after data pre-processing for count-type data.

Results

In this study, we propose to analyze DNA-seq data based on the related distance-type measure. Distances are measured in base pairs (bps) between two adjacent alignments of short reads mapped to a reference genome. Our experimental data based simulation study confirms the advantages of distance-type measure approach in both detection power and detection accuracy. Furthermore, we propose artificial censoring for the distance data so that distances larger than a given value are considered potential outliers. Our purpose is to simplify the pre-processing of DNA-seq data. Statistically, we consider a mixture of right censored geometric distributions to model the distance data. Additionally, to reduce the GC-content bias, we extend the mixture model to a mixture of generalized linear models (GLMs). The estimation of model can be achieved by the Newton-Raphson algorithm as well as the Expectation-Maximization (E-M) algorithm. We have conducted simulations to evaluate the performance of our approach. Based on the rank based inverse normal transformation of distance data, we can obtain the related z-values for a follow-up analysis. For an illustration, an application to the DNA-seq data from a pair of normal and tumor cell lines is presented with a change-point analysis of z-values to detect DNA copy number alterations.

Conclusion

Our distance-type measure approach is novel. It does not require either a fixed or a sliding window procedure for generating count-type data. Its advantages have been demonstrated by our simulation studies and its practical usefulness has been illustrated by an experimental data application.

     

A hypothetical complex between crystalline flavocytochrome b2 and Cytochrome c

Flavocytochrome b₂ and cytochrome c are physiological electron transfer partners in yeast mitochondria. The formation of a stable complex between them has been demonstrated both in solution and in the crystalline state. On the basis of the three-dimensional structures, using molecular modeling and energy minimization, we have generated a hypothetical model for the interaction of these redox partners in the crystal lattice. General criteria such as good charge and surface complementarity, plausible orientation, and separation distance of the prosthetic groups, as well as more specific criteria such as the stoichiometry determined in the crystal, and the involvement of both domains and of more than one subunit of flavocytochrome b₂ led us to discriminate between several possible interaction sites. In the hypothetical model we present, four cytochrome c molecules interact with a tetramer of flavocytochrome b₂. The b₂ and c hemes are coplanar, with an edge-to-edge distance of 14 Å. the contact surface area is ca. 800 Ų. Several electrostatic interactions involving the flavin and the heme domains of flavocytochrome b₂ stabilize the binding of cytochrome c. © 1993 Wiley-Liss, Inc.     

Spermatozoon Ultrastructure in Two Species of Amphibolus (Eutardigrada,Eohypsibiidae)

We examined the ultrastructure of the spermatozoa from two species of eutardigrades, gonochoristic Amphibolus volubilis and hermaphroditic A. weglarskae, by scanning and transmission electron microscopy. The gametes from the two species were morphologically quite similar, each consisting of a short head, neck and tail. The head included a conic, corkscrew-shaped, bilayered acrosome and a cylindrical nucleus with condensed chromatin. The nucleus is surrounded by cytoplasm organized in ovoid elements with an electron-dense core. The neck is very simple, containing a centriole and unmodified mitochondria. The flagellum contains a 9+2 axoneme and terminates in a tuft of between eight and 10 microtubules. The spermatozoa of Amphibolus, like those of the other eutardigrades, are of the modified type, but nonetheless maintain some primitive aspects of the gametes from heterotardigrades.     

PATTERNS OF ALLOZYME RELATIONSHIPS COMPARED WITH MORPHOLOGY,HYBRIDIZATION, AND GEOLOGIC HISTORY IN ALLOPATRIC ISLAND-DWELLING MOSQUITOES

Allozyme relationships were compared with morphology, interspecific hybridization, and geologic history in 14 closely-related species in the Aedes (Stegomyia) scutellaris subgroup. The phylogeny generated by the electrophoretic data was generally in agreement with morphological classifications except that one morphologically distinct species pair (A. alcasidi and A. malayensis) showed only populational differentiation and several nearly identical morphological pairs in Polynesia (e.g., A. pseudoscutellaris and A. polynesiensis) were very distant genetically. A molecular clock, based on the ratio between genetic distance and divergence time (one unit of Nei's distance = 11 million years) inferred from a dated geologic event, was used to compare zoogeography, morphology, and biochemical relationships. Genetic distances between species from the Solomon Islands and the Vanuatu-Polynesia area correspond to an early Pliocene separation of these areas. An invasion of Micronesia occurred approximately 5 million years ago. Most remaining speciation occurred during the mid-Pliocene as islands moved into their present-day positions. The close relationship between southeast Asian and Philippine species could have resulted from the recent onset of isolation in the Pleistocene. Interspecific hybridization potential was not significantly correlated with Nei's genetic distance. Many quite distantly related species readily hybridize, while some closely related pairs show only unidirectional compatibility. Slight interspecific morphological divergence and the independence of hybridization capabilities from phylogeny are not unexpected in a group in which species are allopatric and occupy similar habitats.     

Global Potential Energy Minima of SPC/E Water Clusters without and with Induced Polarization Using a Genetic Algorithm

The global minimum potential energy structures of water clusters, (H₂O) _n , n = 2-14, have been calculated for the SPC/E (Simple Point Charge/Extended) model and a recent fluctuating charge version of the latter using a simple genetic algorithm. The SPC/E cluster geometries are in good agreement with previous TIP3P (Transferable Intermolecular Potential-3 Point) and TIP4P (Transferable Intermolecular Potential-4 Point) calculations as well as the interpretation of experimental measurements. In contrast to this, the polarizable version of the SPC/E model, which is based on the fluctuating charge approach, deviates rather strongly for n=6 with few exceptions. However, comparing the polarizable model to ab initio results for identical cluster geometries we find reasonable agreement for the magnitude of the average molecular dipole moment, the corresponding energy per molecule, and the average oxygen-oxygen distance as functions of n.Electronic Supplementary Material available.     

Egg shell quality,clutch size and hatching success of the great tit (Parus major) and the pied flycatcher (Ficedula hypoleuca) in an air pollution gradient

Egg shell thickness, egg volume, clutch size and hatching success of Parus major and Ficedula hypoleuca were studied at 14 study sites around a copper smelter complex in Harjavalta, south-west Finland, in 1991–1993. In 1991–1992 unhatched eggs were collected to measure shell quality. F. hypoleuca was more susceptible to pollutants than P. major, the response of which was weaker in all aspects studied. Egg shells of F. hypoleuca were about 17% thinner and eggs were about 8% smaller in volume near the factory than at a distance of 10 km. The clutch size of F. hypoleuca was significantly smaller and hatching success markedly lower at a study site next to the factory complex than at all other sites. In P. major, variation in shell thickness and egg volume was not significantly related to the distance from the pollution source. Clutch size and hatching success of P. major did not significantly differ among study sites, although the trend in hatching success was in the same direction as in F. hypoleuca. Clutches of both species contained less shell material and both species had more nests without eggs near the factory than further away. The surface structure of the eggshells was studied by scanning electron microscope. Especially in F. hypoleuca, the egg shell surface was more rough and porous near the factory. The roles of Ca and heavy metals in shell thinning are discussed.     

The Size of DNA Molecules and Chromatin Organization in the Macronucleus of the Ciliate Didinium nasutum (Ciliophora)

Pulsed‐field gel electrophoresis (PFGE) was applied to analyze the molecular karyotype of the ciliate Didinium nasutum. The data obtained indicate that D. nasutum belongs to the ciliate species with subchromosomal macronuclear genome organization. No short “gene‐sized” DNA molecules were detected. Macronuclear DNAs formed a continuous spectrum from 50 kbp to approximately 1,000 kbp in size with a peak plateau between 250 and 400 kbp. The macronuclear DNA molecules were packed into chromatin bodies of 80–265 nm in size. Comparison of the PFGE and electron microscopic data shows that most if not all chromatin bodies contain more than one DNA molecule.     

Study of curcumin behavior in two different lipid bilayer models of liposomal curcumin using molecular dynamics simulation

Liposomal formulation of curcumin is an important therapeutic agent for the treatment of various cancers. Despite extensive studies on the biological effects of this formulation in cancer treatment, much remains unknown about curcumin–liposome interactions. Understanding how different lipid bilayers respond to curcumin molecule may help us to design more effective liposomal curcumin. Here, we used molecular dynamics simulation method to investigate the behavior of curcumin in two lipid bilayers commonly used in preparation of liposomal curcumin, namely dipalmitoylphosphatidylcholine (DPPC) and dimyristoylphosphatidylglycerol (DMPG). First, the free energy barriers for translocation of one curcumin molecule from water to the lipid bilayer were determined by using the potential of mean force (PMF). The computed free energy profile exhibits a global minimum at the solvent–headgroup interface (LH region) for both lipid membranes. We also evaluated the free energy difference between the equilibrium position of curcumin in the lipid bilayer and bulk water as the excess chemical potential. Our results show that curcumin has the higher affinity in DMPG compared to DPPC lipid bilayer (?8.39 vs. ?1.69 k_BT) and this is related to more hydrogen bond possibility for curcumin in DMPG lipid membrane. Next, using an unconstrained molecular dynamic simulation with curcumin initially positioned at the center of lipid bilayer, we studied various properties of each lipid bilayer system in the presence of curcumin molecule that was in full agreement with PMF and experimental data. The results of these simulation studies suggest that membrane composition could have a large effect on interaction of curcumin–lipid bilayer.     

Computational characterisation of the charge-transfer and T-shaped molecular complexes of N-methyl imidazoline-2-thione and N-methyl imidazolidine-2-thione with the dihalogens Br2 and I2

The computational characterisation of the molecular complexes of N-methyl imidazoline-2-thione (methimazole) and the related saturated analogue N-methyl imidazolidine-2-thione with Br₂ and I₂ is carried out using quantum mechanical electronic structure methods. Two kinds of molecular connectivity have been examined. The first displays a collinear S–X–X geometry (X = Br, I) and leads to charge-transfer (CT) type adducts, possible in two stereoisomeric conformations depending on the direction of the X₂-axis, either planar or perpendicular to the NCS plane. The second kind corresponds to T-shaped hypervalent complexes in which sulphur is connected to both the X atoms forming the linear X–S–X arrangement. The structural changes, the spectroscopic findings, the natural bond orbital analysis and the examination of the molecular orbital second-order perturbation energies give interesting information about the nature of the halogen bonding interaction between the electron-donor organic species and the electron-acceptor dihalogen molecule. Similar trends are followed by the energy and relative stability results including basis set superposition error corrections, which show the larger stabilisation of the planar CT conformers of both dihalogens vs. the perpendicular configurations. They also indicate the higher stability of the T-shaped bromine complexes relative to the CT species, opposite to the energy order of the corresponding diiodine adducts. A critical comparison is carried out with literature results on similar systems.