Monomeric Configuration Research Articles

Statistical Molecular Dynamics Study of (111) and (100) Ni Nanocontacts: Evidences of Pentagonal Nanowires

We present molecular dynamics calculations on the evolution of Ni nanowires stretched along the (111) and (100) directions, and at two different temperatures. Using a methodology similar to that required to build experimental conductance histograms, we construct minimum crosssection histograms H(Sm). These histograms are useful to understand the type of favorable atomic configurations appearing during the nanowire breakage. We have found that minimum crosssection histograms obtained for (111) and (100) stretching directions are rather different. When the nanowire is stretched along the (111) direction, monomer and dimer‐like configurations appear, giving rise to well‐defined peaks in H(Sm). On the contrary, (100) nanowire stretching presents a different breaking pattern. In particular, we have found, with high probability, the formation of staggered pentagonal nanowires, as it has been reported for other metallic species.

Scattering and radiative properties of complex soot and soot-containing aggregate particles

We use the superposition T-matrix method to compute the scattering matrix elements and optical cross-sections for a variety of complex soot and soot-containing aggregate particles in random orientation at a visible wavelength 0.628 μm. It is shown that random variations in the geometrical configuration of monomers in a soot cluster for fixed fractal dimension and prefactor, monomer size, and number of monomers have a rather weak effect on scattering and absorption, at least in the visible part of the spectrum. Thus, the electromagnetic scattering and absorption characteristics of a single cluster realization are sufficient to represent the mean values obtained by averaging over many realizations of the “equivalent” clusters generated for the same fractal parameters. However, the results for the soot clusters differ fundamentally from those calculated for the volume-equivalent soot sphere and for the corresponding external mixture of soot monomers, assuming that there are no electromagnetic interactions between the monomers. We also compute and analyze the scattering and absorption properties of aerosols formed by semi-external aggregation of larger ammonium sulfate, silica, or dust particles with soot clusters as well as semi-external aggregates consisting of several components with different sizes and refractive indices. Depending on its chemical composition and size, the larger particle that is in touch with a soot cluster can strongly influence, or even dominate, the overall optical characteristics of the aggregate. Aggregation can result in stronger extinction, absorption, and scattering cross-sections relative to those computed for the corresponding external mixture. Possibly owing to mutual shadowing, the optical cross-sections of multi-component aggregates are smaller than those of their externally mixed counterparts, but by no more than ∼20%. Implications of our study for analyses of remote sensing observations and atmospheric radiation balance computations are discussed.

Computational Studies of Tryptophanyl-tRNA Synthetase: Activation of ATP by Induced-Fit

Catalysis of amino acid activation by Bacillus stearothermophilus tryptophanyl-tRNA synthetase involves three allosteric states: (1) Open; (2) closed pre-transition state (PreTS); and (3) closed products (Product). The interconversions of these states entail significant domain motions driven by ligand binding. We explore the application of molecular dynamics simulations to investigate ligand-linked conformational stability changes associated with this catalytic cycle. Multiple molecular dynamics trajectories (5 ns) for 11 distinct liganded and unliganded monomer configurations show that the PreTS conformation is unstable in the absence of ATP, reverting within ∼600 ps nearly to the Open conformation. In contrast, Open and Product state trajectories were stable, even without ligands, confirming the previous suggestion that catalysis entails destabilization of the protein conformation, driven by ATP-binding energies developed as the PreTS state assembles during induced-fit. The simulations suggest novel mechanistic details associated with both induced-fit (Open-PreTS) and catalysis (PreTS-Product). Notably, Mg 2+–ATP interactions are coupled to interactions between ATP and active-site lysine side-chains via mechanisms that cannot be captured under the molecular mechanics approximations, and which therefore require restraining potentials for stable simulation. Simulations of Mg 2+·ATP-bound PreTS complexes with restraining potentials and with a virtual K111A mutant confirm that these coupling interactions are necessary to sustain the PreTS conformation and, in turn, provide a new model for how the PreTS conformation activates ATP for catalysis. These results emphasize the central role of the PreTS state as a high-energy intermediate structure along the catalytic pathway and suggest that Mg 2+ and the KMSKS loop function cooperatively during catalysis.

Regulation of the immunoglobulin heavy chain locus expression at the phylogenetic level of a bony fish: Transcription factor interaction with two variant octamer motifs

Transcriptional control of the IGH locus in teleosts is not fully understood, but evidence from catfish and zebrafish indicates major roles for octamer-binding (Oct) and E-protein transcription factors. A pair of variant octamer motifs in the Eμ3′ enhancer of the catfish has been shown to be particularly important in driving expression, justifying detailed study of their function. These octamer motifs were examined to determine if they bound Oct2 POU domains in monomeric or dimeric (PORE and MORE) configurations. While catfish Oct2 was shown to be capable of binding PORE and MORE motifs in dimeric conformation, the two octamer motifs in Eμ3′ bound Oct2 POU domains only in monomeric configuration. Catfish Oct2, when bound in this monomeric conformation, was shown to bend the DNA helix. The relative position of the two octamer motifs in Eμ3′ affected the activity of the enhancer, and moving the octamer motifs closer together by 5 bp greatly reduced the activity of the enhancer. This effect was not due to steric hindrance preventing the binding of Oct transcription factors to the two motifs, but rather was shown to be due to the disruption of an additional transcription factor binding site lying between the two octamer motifs.

Configurational Effects in Statistical Theory of Branched Non-Random Polycondensation

The statistical theory of gelation in the simplest process of the non-random polycondensation (S. I. Kuchanov, T. V. Zharnikov, J. Stat. Phys., 111(5/6), 1273 (2003)) has been refined as to be able to take into account the effect of a monomer configuration on topological characteristics of the polymer network of the gel. Proceeding from the kinetic analysis of such a polycondensation, we rigorously prove that it can be described in terms of some stochastic branching process. The parameters of the process depend on the overall number of functional groups in the monomer as well as on the pattern of their mutual arrangement. Examples of some model systems illustrate the effect of kinetic and configurational factors on the topology of a polymer network formed in the course of non-random polycondensation.

Monomeric Fc Fusions

The delivery of therapeutic proteins by noninvasive routes of administration has been a challenging goal, hence current modes of delivery generally require injections. However, we have recently shown that a naturally occurring receptor, the neonatal Fc receptor (FcRn) can be utilized to carry aerosolized therapeutic proteins conjugated to a portion of its respective ligand (Fc domain of immunoglobulin G) across epithelial cells of the lung to effectively deliver biologically active molecules to the bloodstream. First-generation dimeric Fc fusion molecules were successfully transported by the pulmonary route and biologic activity was demonstrated in both non-human primates and human volunteers. Continuing efforts to improve transport efficiency have led to the development of an alternate configuration of Fc fusion proteins with improved characteristics. These second generation Fc fusion molecules are monomeric with respect to the therapeutic protein and dimeric with respect to the Fc region, and have been termed Fc fusion 'monomers'. Several different Fc fusion monomers have demonstrated improved transport efficiency, achieving high bioavailabilities for pulmonary delivery in non-human primates. While the traditional dimeric Fc fusion molecule generally increases the half-life compared with the unconjugated effector molecule, the monomer configuration has been shown to result in an even greater extension of the circulating half-life, which improves pharmacokinetic parameters for protein therapeutics, whether administered by pulmonary delivery or injection. Finally, many of the Fc monomer fusions have enhanced biologic activity compared with the dimeric configuration. Because of these many advantages, the monomer configuration promises to be an enabling advance to achieve clinically relevant, noninvasive delivery with potentially less frequent administration regimens for a broad range of protein therapeutics. In addition, molecules that are comprised of heterodimeric subunits or multi-subunit complexes can also be constructed as Fc fusions that result in a molecule with enhanced pharmacokinetics and greater bioactivity. Several examples of novel Fc fusion proteins, both monomer and heterodimer are described herein.

Three-dimensional models for homogeneous DNA near denaturation

Motivated by the melting transition of DNA, we study genuinely three-dimensionalmodels for two interacting open, flexible and homogeneous macromolecularchains, bound or unbound to each other, at thermal equilibrium fromabout room temperature up to about the denaturation temperature(Tun). In each chain, angular constraints on bond angles (due tocovalent bonding) determine monomers: each monomer containsne nucleotides and hasan effective length de. These monomers could remain practically unaltered for temperatures in a range above and belowTun, down to 300 K.Estimates for ne and de are provided and justified. Upon proceeding from Quantum Mechanics to theclassical limit and using suitable large-distance approximations (partly, due tothose monomer configurations), we get a generalization of Edwards’ model, whichincludes effective potentials between monomers. The classical partition function forthe two-chain system is reduced to an integral of a generalized and discretizedtwo-chain Green’s function. We analyse conditions for the denaturing transition.The fact that each single chain is an extended one-dimensional system modifiestheir mutual global interaction, in comparison with typical potentials betweennucleotides: this is simply illustrated by computing a global effective potentialbetween the two chains. Applications for Morse potentials are presented. Ourmodels seem to be physically compatible with some previous one-dimensional onesand could allow us to efficiently extend the latter to three spatial dimensions.

Competing hydrogen bond topologies in 2-fluoroethanol dimer

Isolated 2-fluoroethanol exists predominantly as a pair of enantiomeric all- gauche conformations, which are stabilized by an intramolecular O–H⋯F interaction. Its most stable OH⋯OH hydrogen-bonded dimers differ in their relative monomer configuration and in their network of weak intermolecular interactions involving the electronegative fluorine atoms. OH-stretching FTIR spectra of supersonic jet expansions using He as a carrier gas reveal four dimer isomers. Only two isomers survive upon Ar admixture. Exploratory quantum chemical calculations confirm that the two surviving conformations involve insertion of the OH group of one monomer into the intramolecular O–H⋯F interaction of the other. The two unstable conformations consist of more loosely associated monomers. Chiral recognition leads to different OH stretching wavenumbers for homo- and heteroconfigurational dimers, but both are formed in similar quantities in the jet expansion.

Polymer Crystal Engineering for Control of Stereochemical Structure of Polymers: Stereospecific Monomer Synthesis and Stereospecific Solid-State Polymerization

ABSTRACT We have successfully synthesized diisotactic and disyndiotactic polymers of (Z,Z)- and (E,E)-muconates with various benzyl ester groups. Muconic acid was conveniently converted into its corresponding ester derivatives without EZ isomerization when reacted with benzyl bromides in the presence of potassium carbonate in hexamethylphosphoramide (HMPA) at room temperature. Several monomers undergo photopolymerization in the crystalline state to give stereoregular polymers according to the monomer configuration and the ester substituents. X-ray single crystal structure analysis of the monomer and polymer crystals has revealed the process of the topochemical polymerization. In the monomer crystals with 4-alkoxybenzyl groups as the ester substituents, a columnar structure is formed by the alternate stacking of monomer molecules with the aid of weak hydrogen bonds such as CH/π and CH/O intermolecular interactions. The alternate stacking is appropriate for syndiotactic polymerization, being different from the crystal structures of many other ester monomers which provide a diisotactic polymer due to the translational monomer stacking in a column, as is seen in the crystals of the 4-chloro-, 4-bromo-, and 4-nitro-substituted benzyl esters. Weak and flexible intermolecular interactions provide a variety of crystal structures and different type of molecular stacking leading to the different tacticity of the polymers.

The Procapsid Binding Domain of φ29 Packaging RNA Has a Modular Architecture and Requires 2‘-Hydroxyl Groups in Packaging RNA Interaction

The phi29 packaging RNA (pRNA) is an essential component in the phi29 bacteriophage DNA packaging motor, the strongest biomolecular motor known today. Utilizing Mg2+-dependent intermolecular base pairing interactions between two 4-nucleotide loops within the pRNA procapsid binding domain, multiple copies of pRNA form a ring-shaped complex that is indispensable for packaging motor function. To understand pRNA structural organization and pRNA/pRNA interaction, studies were carried out on pRNA closed dimers, the simplest functional pRNA complex believed to be the building blocks for assembling the oligomeric ring. Tertiary folding and interactions in various pRNA mutants were evaluated based on measured closed dimer affinity that is directly linked to the proper positioning of the interacting loops. The data revealed that the procapsid binding domain contains two autonomous modules that are capable of interacting noncovalently to form a fully active species in pRNA/pRNA interaction. Deleting the 2'-hydroxyl groups in one of the interacting loops weakens the dimer affinity by 125-fold, suggesting potential tertiary interactions involving these 2'-hydroxyl groups. The results provide evidence that nonbase functional groups are involved in pRNA folding and interaction and lead to a simple model that describes the pRNA monomer configuration in terms of three arms spanning a hinge. The functional constructs developed here will aid biophysical and biochemical investigations of pRNA structure and function, as well as developments of pRNA-based technology for nanoscience and gene therapy.

OBF1 enhances transcriptional potential of Oct1.

The POU transcription factors Oct1 and Oct2 bind to DNA in various monomer and dimer configurations. Depending on the DNA sequence to which they bind, the dimers are arranged in configurations that are either accessible (PORE sequence) or inaccessible (MORE sequence) to the B-cell-specific cofactor OBF1 (OcaB, Bob1). As shown previously, the MORE and related sequences (such as the heptamer/octamer motif) are found in immunoglobulin heavy chain promoters. Here we show that the expression of Osteopontin, which contains a PORE sequence in its enhancer region, depends on the presence of OBF1 in B cells. OBF1 alleviates DNA sequence requirements of the Oct1 dimer on PORE-related sequences in vitro. Furthermore, OBF1 stabilizes POU dimer-DNA interactions and overrides Oct1 interface mutations, which abolish PORE-mediated dimerization without OBF1. Our data indicate that the PORE-type Oct1 or Oct2 dimer, rather than the monomer, is the primary target of the cofactor OBF1. Based on our biochemical data, we propose a mode of OBF1-Oct1 dimer interaction, suggesting a novel arrangement of the subdomain connectivities.

2'-Spiro ribo- and arabinonucleosides: synthesis, molecular modelling and incorporation into oligodeoxynucleotides.

We have synthesized four conformationally restricted bicyclic 2'-spiro nucleosides via 2'-C-allyl nucleosides as key intermediates. The ribo-configured 2'-spironucleosides 9b and 14b were obtained by a convergent strategy starting from 2-ketofuranose 1 whereas the arabino-configured 2'-spironucleosides 21 and 27 were obtained by a linear strategy with a 2'-ketouridine derivative as starting material. The furanose ring of 9b/14b adopts N-type conformations whereas the furanose ring of 21/27 exists as an N<==>S equilibrium. These compounds showed no anti-HIV-1 activity or cytotoxicity. Incorporation of the four 2'-spironucleosides (as monomers X4 and X5) into oligodeoxynucleotides was accomplished using the phosphoramidite approach on an automated DNA synthesizer. Irrespective of monomeric configuration, hybridization studies revealed that these 2'-spironucleotide monomers (X4 and X5) induce decreased duplex thermostabilities compared with the corresponding DNA:DNA and DNA:RNA duplexes. Molecular modelling indicated that steric constraints are a possible reason for the lowered binding affinities of the modified oligodeoxynucleotides towards complementary single-stranded DNA and single-stranded RNA complements.

Dipolar interaction in (NH 3.6 D 0.4 ) 2 PtCl 6

At 10% deuteration ammonium hexachloroplatinate stays in its cubic phase Fm3m at all temperatures. Rotational tunneling of NH4 and NH3D was measured by neutron spectroscopy. At temperatures T≥18 K, energies and intensities of the observed tunneling transitions agree with a statistical occurrence of ammonium isomers in a tetrahedral environment. Below T=18 K there is almost no change of the NH4 lines, while the NH3D line passes through an unresolved broad intensity distribution to a new three-line low-temperature spectrum. The intermediate spectrum is interpreted as the dynamical average of long-range dipolar-coupled orientationally disordered NH3D ions. The low-temperature spectra find an explanation as frozen minimum-energy configurations of NH3D monomers and dimers. A dipole moment of NH3D of 0.05 D can be estimated from the difference of the tunnel splittings.

Aggregation of defects in Ho3+-doped fluorite crystals

Low Ho3+ concentrations (∼0.01%) yield only the 1∣11 and 1∣12 (monomer) configurations of Ho3+–F– centres in both CaF2 and SrF2 crystals. The 1∣11 and 1∣12 configurations correspond to the charge compensating F– ion occupying the nearest neighbour and next nearest neighbour position respectively, relative to the Ho3+ ion. For CaF2:Ho3+ crystals, the two monomer centres occur with comparable densities while the 1∣11 centre is dominant in SrF2:Ho3+ crystals. At moderate Ho3+ concentrations (∼0.1%), Ho3+ dimer centres are dominant in both CaF2 and SrF2 and the population of monomer centres is significantly reduced. In CaF2:Ho3+, the 2∣21 and 2∣22 configuration dimer centres occur in comparable densities; these rhombic centres are formed by preferential aggregation of the 1∣11 and 1∣12 configuration centres, respectively. A third dimer centre, of the 2∣31 configuration, also appears in CaF2. Only the 2∣21 and 2∣31 configuration centres are present in similarly doped SrF2 crystals. The type and population of dimer centres that form in Ho3+–doped fluorite crystals depend on the monomer centre(s) favoured by the particular lattice. The crystalfield energy level structures of the 2∣21 and 2∣31 configuration centres are consistent with weaker crystal field effects, particularly in CaF2, compared to the parent 1∣11 centre; those of the 2∣22 and 1∣12 centres are comparable.

Synergism with the Coactivator OBF-1 (OCA-B, BOB-1) Is Mediated by a Specific POU Dimer Configuration

POU domain proteins contain a bipartite DNA binding domain divided by a flexible linker that enables them to adopt various monomer configurations on DNA. The versatility of POU protein operation is additionally conferred at the dimerization level. The POU dimer formed on the PORE (ATTTGAAATGCAAAT) can recruit the transcriptional coactivator OBF-1, whereas POU dimers formed on the consensus MORE (ATGCATATGCAT) or on MOREs from immunoglobulin heavy chain promoters (AT[G/A][C/A]ATATGCAA) fail to interact. An interaction with OBF-1 is precluded since the same Oct-1 residues that form the MORE dimerization interface are also used for OBF-1/Oct-1 interactions on the PORE. Our findings provide a paradigm of how specific POU dimer assemblies can differentially recruit a coregulatory activity with distinct transcriptional readouts.

Influence of the stereochemical configuration on the radical polymerization of methacrylic monomers:cis- andtrans-(2-cyclohexyl-1,3-dioxan-5-yl) methacrylate

The synthesis of two new isomeric monomers, cis-(2-cyclohexyl-1,3-dioxan-5-yl) methacrylate (CCDM) and trans-(2-cyclohexyl-1,3-dioxan-5-yl) methacrylate (TCDM), starting from the reaction of glycerol and cyclohexanecarbaldehyde, is reported. The process involved the preparation of different alcohol acetals and esterification with methacryloyl chloride of the corresponding cis and trans 5-hydroxy compounds of 2-cyclohexyl-1,3-dioxane. The radical polymerization reactions of both monomers, under the same conditions of temperature, solvent, monomer, and initiator concentrations, were studied to investigate the influence of the monomer configuration on the values of the propagation and termination rate constants (kp and kt ).The values of the ratio kp /kt 1/2 were determined by UV spectroscopy by the measurement of the changes of absorbance with time at several wavelengths in the range 275–285 nm, where an appropriate change in absorbance was observed. Reliable values of the kinetics constants were determined by UV spectroscopy, showing a very good reproducibility of the kinetic experiments. The values of kp /kt 1/2, in the temperature interval 45–65 °C, lay in the range 0.40–0.50 L1/2/mol1/2s1/2 and 0.20–0.30 L1/2/mol1/2s1/2 for CCDM and TCDM, respectively. Measurements of both the radical concentrations and the absolute rate constants kp and kt were also carried out with electron paramagnetic resonance techniques. The values of kp at 60 °C were nearly identical for both the trans and cis monomers, but the termination rate constant of the trans monomer was about three times that of the cis monomer at the same temperature. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 3883–3891, 2000

The cartilage-specific (V+C)− fibronectin isoform exists primarily in homodimeric and monomeric configurations

Fibronectin is an extracellular-matrix glycoprotein encoded by a single gene, but with significant protein heterogeneity introduced through alternative RNA splicing and post-translational modifications. The (V+C)- splice variant, in which nucleotides encoding protein segments III-15 and I-10 are deleted along with the entire variable region, is unique in that expression is restricted to cartilaginous tissues. All known fibronectin splice variants retain the two C-terminal cysteine residues essential for dimerization, but cellular and/or structural constraints appear to influence homo- and heterodimerization patterns. Dimerization patterns of the (V+C)- isoform were studied under native conditions within canine articular cartilage and experimentally in COS-7, NIH-3T3 and CHO-K1 cell cultures. In all systems, (V+C)- fibronectin secretion was predominantly in a homodimeric configuration. Lower levels of (V+C)- monomers were also present. Heterodimers of (V+C)- with V+,C+ (V120) isoforms were not detected. Heterodimers of (V+C)- with V-,C+ (V0) subunits were detected only at low levels. Functional properties may differ significantly among monomers, homodimers and heterodimers. The unique dimerization pattern of (V+C)- fibronectin is consistent with this isoform having specialized functional properties in situ that are important for either the structural organization and biomechanical properties of cartilage matrix or regulation of a chondrocytic phenotype.

The cartilage-specific (V+C)− fibronectin isoform exists primarily in homodimeric and monomeric configurations

Fibronectin is an extracellular-matrix glycoprotein encoded by a single gene, but with significant protein heterogeneity introduced through alternative RNA splicing and post-translational modifications. The (V+C)(-) splice variant, in which nucleotides encoding protein segments III-15 and I-10 are deleted along with the entire variable region, is unique in that expression is restricted to cartilaginous tissues. All known fibronectin splice variants retain the two C-terminal cysteine residues essential for dimerization, but cellular and/or structural constraints appear to influence homo- and heterodimerization patterns. Dimerization patterns of the (V+C)(-) isoform were studied under native conditions within canine articular cartilage and experimentally in COS-7, NIH-3T3 and CHO-K1 cell cultures. In all systems, (V+C)(-) fibronectin secretion was predominantly in a homodimeric configuration. Lower levels of (V+C)(-) monomers were also present. Heterodimers of (V+C)(-) with V(+),C(+) (V120) isoforms were not detected. Heterodimers of (V+C)(-) with V(-),C(+) (V0) subunits were detected only at low levels. Functional properties may differ significantly among monomers, homodimers and heterodimers. The unique dimerization pattern of (V+C)(-) fibronectin is consistent with this isoform having specialized functional properties in situ that are important for either the structural organization and biomechanical properties of cartilage matrix or regulation of a chondrocytic phenotype.

Rigid-Rod Polyimides Based on Noncoplanar 4,4‘-Biphenyldiamines: A Review of Polymer Properties vs Configuration of Diamines

X-ray crystal structures of three substituted 4,4‘-biphenyldiamines, namely, 2,2‘,6,6‘-tetramethylbenzidine (TMBZ), 2,2‘-dimethylbenzidine (DMBZ) and 2,2‘-bis(trifluoromethyl)benzidine (BFBZ), were determined. The torsional angles between the two phenyl rings for TMBZ, DMBZ, and BFBZ are φ = 83°, 75°, and 59°, respectively. A structure−property relationship between the three-dimensional configuration of diamine monomers and the corresponding polyimides is discussed.

Specificities of anti-sialyl-Tn and anti-Tn monoclonal antibodies generated using novel clustered synthetic glycopeptide epitopes.

The fine specificities of MAbs generated using novel synthetic clustered STn and Tn glycopeptides as immunogens were compared with the anti-TAG-72 antibodies B72.3 and CC49. Hapten inhibition experiments demonstrated the specificity of several of the MAbs for STn and Tn expressed on ovine submaxillary mucin and tumor derived MUC-1 mucin. Amongst the STn specific MAbs only the B195.3 MAb shows absolute dependence on the presence of sialic acid and specificity to the simple disaccharide NANAA alpha2-6-GalNAc. Identification of tumor associated carbohydrate epitopes in cluster and monomer configurations are possible using MAbs detecting the defined structure specificities described herein.