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The reactions of pyrethrin I, cinerin I and jasmolin I with sodium hydroxide in ethanol afforded an approximately 1:1 ratio of two respective cyclopentadienone dimers, isolated in good yield. A combination of one-dimensional and two-dimensional NMR spectroscopic studies allowed determination of the structure and stereochemistry of the dimers. The dimers are formed by cycloaddition reactions of the less substituted alkene of the cyclopentadienone, and by regioisomeric endo transition states. Density functional theory calculations were in accord with the experimental findings showing the products formed by ambimodal transition states. One such transition state led to two initial products with the less stable product undergoing facile conversion to the other more stable, experimentally observed product. These studies clarify the structures of the altered pyrethrolone reported by Staudinger and Ruzicka in 1924. On treatment with base, the natural pyrethrins pyrethrin I, cinerin I and jasmolin I undergo elimination to transient cyclopentadienones that dimerise to afford regioisomeric endo cycloadducts. (Image credit: J. H. Ryan.) [ABSTRACT FROM AUTHOR]

The bonding between two neutral aromatic compounds, especially small ones, has been controversially debated in the last decades, and terms like "π‐stacking" had to be revised. Surprisingly, despite of many experimental and computational work, there is still no clear consensus about the structure of and the bonding in the pyridine dimer. In this work, for different isomeric forms of the pyridine dimer, the structures and bonding were elucidated by combining high‐resolution matrix‐isolation spectroscopic results with quantum‐chemical calculations. High‐resolution IR spectra of Ne matrices at 4 K containing pyridine were recorded for different concentrations and upon annealing to 10 and 12 K, relying on three isotopologues of pyridine. The spectra show the presence of hydrogen‐bonded, T‐shaped, and stacked forms of weakly‐bound pyridine dimers. Among these, the hydrogen‐bonded isomer is identified as the lowest‐energy form. The results provide for the first time conclusive information about the interaction between two pyridine dimers. [ABSTRACT FROM AUTHOR]

The RAS-regulated RAF–MEK1/2–ERK1/2 pathway promotes cell proliferation and survival and RAS and BRAF proteins are commonly mutated in cancer. This has fuelled the development of small molecule kinase inhibitors including ATP-competitive RAF inhibitors. Type I and type I½ ATP-competitive RAF inhibitors are effective in BRAFV600E/K-mutant cancer cells. However, in RAS-mutant cells these compounds instead promote RAS-dependent dimerisation and paradoxical activation of wild-type RAF proteins. RAF dimerisation is mediated by two key regions within each RAF protein; the RKTR motif of the αC-helix and the NtA-region of the dimer partner. Dimer formation requires the adoption of a closed, active kinase conformation which can be induced by RAS-dependent activation of RAF or by the binding of type I and I½ RAF inhibitors. Binding of type I or I½ RAF inhibitors to one dimer partner reduces the binding affinity of the other, thereby leaving a single dimer partner uninhibited and able to activate MEK. To overcome this paradox two classes of drug are currently under development; type II pan-RAF inhibitors that induce RAF dimer formation but bind both dimer partners thus allowing effective inhibition of both wild-type RAF dimer partners and monomeric active class I mutant RAF, and the recently developed “paradox breakers” which interrupt BRAF dimerisation through disruption of the αC-helix. Here we review the regulation of RAF proteins, including RAF dimers, and the progress towards effective targeting of the wild-type RAF proteins. [ABSTRACT FROM AUTHOR]

N‐Heteropolycycles are among the most promising candidates for applications in organic devices. For this purpose, a profound understanding of the low‐energy electronic absorbance and emission characteristics is of crucial importance. Herein, we report high‐resolution absorbance and fluorescence spectra of pentacene (PEN) and 6,13‐diazapentacene (DAP) in solid neon obtained using the matrix‐isolation technique. Accompanying DFT calculations allow the assignment of specific vibrationally resolved signals to corresponding modes. Furthermore, we present for the first time evidence for the formation of van der Waals dimers of both substances. These dimers exhibit significantly different optical characteristics resulting from the change of electronic properties evoked by the incorporation of sp2 nitrogen into the molecular backbone. [ABSTRACT FROM AUTHOR]

In establishing the sources of data variability within sedimentation velocity analysis in the analytical ultracentrifuge and their relative importance, recent studies have demonstrated that alignment of the sample cells to the centre of rotation is the most significant contributing factor to overall variability, particularly for the characterisation of low levels of protein aggregation. Accurate mechanical and optical alignment tools have been recently designed. In this study, we (1) confirm the effect of misalignment observed by others on the estimated amounts of bovine serum albumin (BSA) monomer and dimer, and the sedimentation coefficient value for the BSA dimer; and (2) demonstrate the high performance of a mechanical alignment tool and the usefulness of a simple and complementary enhanced manual alignment protocol which should be useful for situations where these tools are not available. [ABSTRACT FROM AUTHOR]

Highlights: [•] The role of phosphorylation of Arabidopsis14-3-3ω at Ser62 and Ser67 was studied. [•] Phosphomimetic mutants show gel mobility intermediate between monomers and dimers. [•] Phosphomimetic mutation shifts the monomer–dimer equilibrium towards monomers. [•] Urea, DOC, temperature and pH affect the position of the equilibrium. [•] Phosphomimetic mutants form higher order aggregates when dimers are dissociated. [Copyright &y& Elsevier]

The first total syntheses of Tectona grandis (teak) natural products hemitectol and tectol are described. The observation of spontaneous dimerisation of hemitectol to tectol suggests the monomer is the true natural product and that the dimer is an artifact of isolation. [ABSTRACT FROM AUTHOR]

Abstract: Bacteriophages (phages) produce endolysins (lysins) as part of their lytic cycle in order to degrade the peptidoglycan layer of the infected bacteria for subsequent release of phage progeny. Because these enzymes maintain their lytic and lethal activity against Gram-positive bacteria when added extrinsically to the cells, they have been actively exploited as novel anti-infectives, sometimes termed enzybiotics. As with other relatively small peptides, one issue in their clinical development is their rapid inactivation through proteolytic degradation, immunological blockage and renal clearance. The antipneumococcal lysin Cpl-1 was shown to escape both proteolysis and immunological blockage. However, its short plasma half-life (20.5min in mice) may represent a shortcoming for clinical usefulness. Here we report the construction of a Cpl-1 dimer with a view to increasing both the antipneumococcal specific activity and plasma half-life of Cpl-1. Dimerisation was achieved by introducing specific cysteine residues at the C-terminal end of the enzyme, thus favouring disulphide bonding. Compared with the native monomer, the constructed dimer demonstrated a two-fold increase in specific antipneumococcal activity and a ca. ten-fold decrease in plasma clearance. As several lysins are suspected to dimerise on contact with their cell wall substrate to be fully active, stable pre-dimerised enzymes may represent a more efficient alternative to the native monomer. [Copyright &y& Elsevier]

Abstract: Alternative channels of the tungsten imido-catalysed olefin dimerisation proceeding through mono(imido) and bis(imido) compounds have been examined by means of the DFT method simulating authentic reaction conditions on catalyst models that closely mimic the real catalyst system. All relevant steps of a plausible metallacycle mechanism to follow alternative pathways together with the divergent path towards azatungstanacycle intermediates have been characterised by considering up to three AlClMe2 moieties explicitly. This study disclosed that the Lewis acid is actively engaged in the productive catalytic cycle, this in addition to its presumed role, among others, as alkylating and chloride ligand abstraction agent in the formation of the active catalyst species. The Lewis acid preferably forms four-membered chelates across tungsten–imido or tungsten–chlorine bonds featuring a μ-Al–Cl–W bridge. The formation of the five-membered tungstanacycle is found to be less affected by the cocatalyst, but it acts profoundly in modulating the energetics of its degradation into the dimer product. DFT predicts a smooth energy profile for the most accessible path via mono(imido) tungsten species, having the Lewis acid bridged across tungsten–chlorine bonds, which is in consonance with observed activity and selectivity. This type of Lewis acid association appears as being pivotal for an effective catalysis. The alternative channel to engage bis(imido) tungsten compounds features significantly more demanding kinetics for the dimer generating route, thereby rendering it as being almost impossible to be accessed. The present study constitutes evidence, based on reliable DFT calculations, that mono(imido) tungsten compounds complexed by the Lewis acid component is effectively triggering dimerisation, whilst bis(imido) tungsten species are unlikely to play a role in the productive cycle. [Copyright &y& Elsevier]

The formation of hydrogen-bonded dimeric capsules from tetraurea calix[4]arenes is controlled by loops, connecting adjacent urea functions, and more or less bulky substituents. The dimerisation is only possible if loops are not overlapping and if the respective residues can pass the loops. A sorting scheme based on small and bulky residues and one to four loops allows reducing the number of possible dimers from 35 to 6 in a stoichiometric mixture of 11 ureas. With three different loop sizes (O-(CH2)n-O chains with n = 10, 14, 20 connecting adjacent phenylurea functions via their meta positions), it is possible to distinguish four urea residues of different sizes (small, medium, bulky and giant) ranging from tolyl to 4-[tris-(4-t-butylphenyl)methyl]-phenyl. While the smallest residue can pass all loops, the largest is excluded by all loops. [ABSTRACT FROM AUTHOR]

Abstract: In this article, we consider the molecular mechanisms that underlie broad-spectrum amino acid sensing by a discrete subgroup of class C G-protein-coupled receptors that includes the calcium-sensing receptor, GPRC6A and heterodimers composed of two closely related receptor subunits, T1R1 and T1R3. We consider their physiological significance highlighting their diverse spectrum of cellular responses and the phenotypes of global and conditional knock-out mice. In addition, we consider strategies for the development of new drugs that target these receptors. [Copyright &y& Elsevier]

Abstract: Somatostatin (SST) is a peptide hormone that acts through a family of heptahelical receptors belonging to the G-protein coupled receptor (GPCR) superfamily. There are five known SST receptor subtypes termed SSTR1–5 and all couple to Gαi/o G-proteins. It has been previously demonstrated that these receptors can form both homo- and heterodimers within their family or with other GPCR family members. Although agonist was demonstrated as a factor in modulating certain dimeric pairs, the molecular mechanism(s) underlying this regulation remains undetermined. Here, we demonstrate the coupling of G-protein as a contributing factor in the homo- and heterodimerisation of human (h) SSTR2 and SSTR5. When cells stably expressing hSSTR2 are pretreated with pertussis toxin (PTX), dissociation of hSSTR2 dimers occurs. Interestingly, although dimerisation of hSSTR5 was unaffected following PTX treatment, heterodimerisation between hSSTR2 and hSSTR5 is potentiated in the absence of receptor-stimulation. These results demonstrate the importance of G-protein in the maintenance and regulation of hSSTR dimers. [Copyright &y& Elsevier]

Abstract: Influence of the intrinsic properties of calixarene ligands on catalytic reactions involving ethylene. This review shows how the particular structural and chemical properties of calix[4]arene-derived ligands can be exploited in the catalytic transformation of ethylene into dimers, oligomers, and polymers. [Copyright &y& Elsevier]

We study theoretically the effect of oligomer formation on secondary organic aerosol (SOA) growth following ozonolysis of-pinene. Our goal is to show qualitatively, using a simplified condensational growth model, that the formation of involatile oligomers can induce the condensation growth of aerosols even if the secondary organic species formed in the oxidation reactions are rather volatile and therefore poorly condensable. The closed system studied consists of a single effective gas-phase oxidation product, and a seed aerosol population consisting of monodisperse ammonium sulphate particles. The oligomer formation is described as an effective dimerisation reaction between the monomers in the aerosol phase. By varying the dimerisation constant until our model results match the results from earlier smog-chamber studies, we are able to make order-of-magnitude estimations of the unknown dimerisation rates needed to induce the observed SOA growth. We also make model simulations using atmospheric-pinene and ozone concentrations, and find that the effective dimerisation rate inducing SOA growth in the atmosphere has to be considerably higher than that causing SOA growth in smog-chamber conditions. [Copyright &y& Elsevier]

Abstract: The regioselective outcome observed during dimerisation of butenolides to dimeric structures via captodative stabilised radicaloids has been studied. The captodative stabilised radicaloids were generated by initial conversion of butenolides to chlorobutenolides via the corresponding hydroxybutenolides, followed by treatment with CoCl(PPh3)3. [Copyright &y& Elsevier]

Abstract: The crystal structure of human phenylethanolamine N-methyltransferase (hPNMT) reveals a disulfide-linked dimer, despite the presence of reducing agent in the crystallisation conditions. By removing the reducing agent, hPNMT crystals grow more rapidly and at lower protein concentrations. However, it was unclear whether the disulfide bonds are only present in the crystal form or whether these affect enzyme activity. The solution oligomeric state of hPNMT was investigated using biochemical techniques and activity assays. We found that in the absence of reducing agent, hPNMT forms dimers in solution. Furthermore, the solution dimer of hPNMT incorporates disulfide bonds, since this form is sensitive to reducing agent. The C48A and C139A mutants of hPNMT, which are incapable of forming the disulfide bond observed in the crystal structure, have a decreased propensity to form dimer in solution. Those dimers that do form are also sensitive to reducing agent. Further, the C48A/C139A double mutant shows only monomeric behaviour. Both dimeric and monomeric hPNMT, as well as mutants have wildtype enzyme activity. These results show that a variety of disulfides, including those observed in the crystal structure, can form in solution. In addition, disulfide-linked dimers are as active as the monomeric enzyme indicating that the crystal structure of the protein is a valid target for inhibitor design. [Copyright &y& Elsevier]

The concept that GPCRs exist and potentially function as dimers and/or higher oligomers has progressed recently from hypothesis to being widely accepted. A range of techniques has contributed to this understanding, including co-immunoprecipitation and various forms of fluorescence and bioluminescence resonance energy transfer. Although co-immunoprecipitation studies indicate the capacity of a wide range of GPCRs to form hetero-dimers as well as homo-dimers, this approach is not well suited to examine selectivity of interactions. Both bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) have been applied to the detection of GPCR dimerisation in intact cells and BRET and FRET have been used to attempt to quantitate the fraction of GPCRs present as dimers. Following heterologous expression, a considerable fraction of many GPCRs is not fully processed and is trafficked to the proteasome or lysosome for destruction. A distinct limitation of both BRET and conventional FRET approaches is that both the energy donor and energy acceptor tags are inside the cell. Time-resolved FRET employing N-terminally epitope-tagged GPCRs has been used to allow detection only of dimers trafficked successfully to the cell surface. Reports indicating the appearance of distinct pharmacology and function following co-expression of two GPCRs are fascinating. Much remains to be examined, however, on the specificity and mechanisms of these interactions and to develop techniques to monitor the function only of hetero-dimers when the corresponding homo-dimers must also be present. [Copyright &y& Elsevier]

The kinetics of the oxidative dehydrodimerisation and aromatisation of isobutene has been studied on a Bi2Sn2O7 system for a mechanistic understanding of the reaction. The rate of disappearance of isobutene has been found to be first order with respect to oxygen and second order with respect to isobutene. A good fit of the kinetic data with the Mars and van Krevelen model has been established. The kred and kox have been found to be 2.3×106 and 32×106 mol min−1 m−2 kPa−1, respectively, proving that the reduction of the catalyst is the rate-determining step. Studies were also done to verify the mechanistic pathway of the reaction. Previous workers have suggested that the reaction is essentially a consecutive reaction proceeding from isobutene to p-xylene through the intermediate dimer (2,5-dimethyl-1,5-hexadiene). Studies were done at increasing contact time to verify the mechanistic pathway of the reaction and the intermediate dimer was used as the reactant. Our results showed that the intermediate dimer is mainly oxidised to COx while p-xylene is formed through some direct parallel pathway from isobutene. [Copyright &y& Elsevier]

The frameshift mutants K192Sfs*7 and R153Sfs*41, of the polyglutamine tract-binding protein 1 (PQBP-1), are stable intrinsically disordered proteins (IDPs). They are each associated with the severe cognitive disorder known as the Renpenning syndrome, a form of X-linked intellectual disability (XLID). Relative to the monomeric wild-type protein, these mutants are dimeric, contain more folded contents, and have higher thermal stabilities. Comparisons can be drawn to the toxic oligomerisation in the "conformational diseases", which collectively describe medical conditions involving a substantial protein structural transition in the pathogenic mechanism. At the molecular level, the end state of these diseases is often cytotoxic protein aggregation. The conformational disease proteins contain varying extents of intrinsic disorder, and the consensus pathogenesis includes an early oligomer formation. We reviewed the experimental characterisation of the toxic oligomers in representative cases. PQBP-1 mutant dimerisation was then compared to the oligomerisation of the conformational disease proteins. The PQBP-1 mutants are unique in behaving as stable soluble dimers, which do not further develop into higher oligomers or aggregates. The toxicity of the PQBP-1 mutant dimers lies in the native functions (in transcription regulation and possibly, RNA splicing) being compromised, rather than proceeding to aggregation. Other examples of stable IDP dimers were discussed and we speculated on the roles of IDP dimerisation in protein evolution. [ABSTRACT FROM AUTHOR]

The CCSD(T)/cc‐pVTZ//CCSD/cc‐pVTZ method is used to determine the geometries and energetics of the isomers HXCY vs HY─CX (XN, P, As; YO, S) and their dimers from chain dimerizations and head‐to‐head or head‐to‐tail [2 + 2] cyclodimerizations. The HO─CX structures with CX triple bonds lie at energies at least 18.5 kcal/mol above their HXCO isomers. However, the energy differences between the HXCS and HS─CX isomers are found to be particularly small, especially in the [H,P,C,S] and [H,As,C,S] systems. For (HNCY)2, the lowest energy dimers are the chain isomers, which lie ~11 kcal/mol below the lowest energy cyclic dimers aNO containing a NCNC ring and cNS containing a NCSC ring. Formation of the remaining dimers through dimerization from two monomers is predicted to be endothermic and thus thermodynamically disfavored. However, the energies of the chain isomers in the other (HXCY)2 (XP, As; YO, S) series are higher than those of the corresponding isomeric lowest energy cyclodimers. For (HXCO)2 (XP, As), the lowest energy structures are the head‐to‐head dimers hPO and hAsO containing a C─C─XX ring. For (HXCS)2 (XP, As), the lowest energy structures are the head‐to‐head dimers gPS and gAsS with a CCXS ring. [ABSTRACT FROM AUTHOR]