Tunneling in the reaction of acetone with OH

Based on recent detailed quantum mechanical computations of the mechanism of the title reaction (Phys. Chem. Chem. Phys., 2003, 5, 333) and (J. Chem. Phys., 2003, 119, 10 600), this paper presents kinetics analysis of the overall rate constant and its temperature dependence, for which ample experimental data are available for comparison. The analysis confirms that the principal channel is the formation of acetonyl radical + H2O, while the channel leading to acetic acid is of negligible importance. It is shown that the unusual temperature dependence of the overall rate constant, as observed experimentally, is well accounted for by standard RRKM treatment that includes tunneling. This treatment is applied at the microcanonical level, with chemically activated distribution of entrance species, i.e. using a stationary rather than a thermal distribution that incorporates collisional energy transfer and competition between the redissociation and exit channel. A similar procedure is applied to the isotopic reaction acetone-d6 + OH with equally satisfying results, so that the experimental temperature dependence of the KIE (kinetic isotope effect) is perfectly reproduced. This very good agreement between calculation and experiment is obtained without any fitting to experimental values and without any adjustment of the parameters of calculation

Relationships between Th1 or Th2 iNKT cell activity and structures of CD1d-antigen complexes: meta-analysis of CD1d-glycolipids dynamics simulations.

A number of potentially bioactive molecules can be found in nature. In particular, marine organisms are a valuable source of bioactive compounds. The activity of an α-galactosylceramide was first discovered in 1993 via screening of a Japanese marine sponge (Agelas mauritanius). Very rapidly, a synthetic glycololipid analogue of this natural molecule was discovered, called KRN7000. Associated with the CD1d protein, this α-galactosylceramide 1 (KRN7000) interacts with the T-cell antigen receptor to form a ternary complex that yields T helper (Th) 1 and Th2 responses with opposing effects. In our work, we carried out molecular dynamics simulations (11.5 µs in total) involving eight different ligands (conducted in triplicate) in an effort to find out correlation at the molecular level, if any, between chemical modulation of 1 and the orientation of the known biological response, Th1 or Th2. Comparative investigations of human versus mouse and Th1 versus Th2 data have been carried out. A large set of analysis tools was employed including free energy landscapes. One major result is the identification of a specific conformational state of the sugar polar head, which could be correlated, in the present study, to the biological Th2 biased response. These theoretical tools provide a structural basis for predicting the very different dynamical behaviors of α-glycosphingolipids in CD1d and might aid in the future design of new analogues of 1

An Atomic Decomposition Scheme of Noncovalent Interactions applied to Host-Guest Assemblies

International audienceThe design of novel stimuli-responsive supramolecular systems based on host-guest chemistry implies a thorough understanding of the noncovalent interactions involved. In this regard, some computational tools enabling the extraction of the noncovalent signatures from local descriptors based on the electron density have been previously proposed. Although very useful to detect the existence of such interactions, these analyses provides only a semi-quantitative description, which represents a limitation. In this work, we present a novel computational tool based on the local atomic descriptor IGM-〖δg〗^(inter/At), able to decompose the fragment interaction into atomic contributions. Then, the role played by each atom in the formation of the host-guest assembly is quantified by an integrated 〖Δg〗^(inter/At) score. Herein, we apply the IGM-〖Δg〗^(inter/At) approach to some challenging systems, including multimetallic arrays, buckycatchers, and organic assemblies. These systems exhibit unique structural features that make it difficult to determine the host/guest atoms that contribute the most to the encapsulation. Here, the 〖Δg〗^(inter/At) score proves to be an appealing tool to shed light on the guest accommodation on a per atom basis, and could be useful in the rational design of more selective target agents. We strongly believe that this novel approach will be useful for experimental teams devoted to the synthesis of supramolecular systems based on host-guest chemistry

Deciphering the complex role of thrombospondin-1 in glioblastoma development

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Development of the first model of a phosphorylated, ATP/Mg²⁺-containing B-Raf monomer by molecular dynamics simulations:A tool for structure-based design

International audienceA model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg2+ binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF_ATP model. Moreover, the structure and activating interactions of this 2pBRAF_ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies

Mechanistic insights into Smiles rearrangement. Focus on π–π stacking interactions along the radical cascade

International audienceThe synthesis of new arene and heteroarene scaffolds of therapeutic interest has generated a renewed interest in the domino radical cyclisation–Smiles. In this work we present a detailed mechanistic investigation of the radical version of a cascade involving a desulfonative Smiles rearrangement on an aromatic ring bearing a sulfonamide linker. Competing routes have been explored to characterize the molecular mechanism of the studied reaction. The knowledge gained from previous experimental observations is explained through the energy profile obtained by means of quantum mechanical calculations. This study answers questions about the rate determining step and the type of mechanism involved (two-step or concerted). Supplementary rate constant calculations as well as quantum molecular dynamics support experimental observations. An IGM-δg analysis performed along the reaction path unveils and quantifies an intramolecular π–π stacking interaction accelerating the reaction. This novel post processing IGM-δg tool based on the electron density, turns out to be useful to monitor and quantify specific intramolecular weak interactions along a reaction path from wave functions. From this mechanistic investigation it turns out that Smiles rearrangement here takes place in two steps rather than in a direct intramolecular radical substitution. Furthermore, we show that chain length effects must be taken into account in the functionalization of new sulfonylated derivatives subjected to this radical cascade, given their influence in the reaction rate

The stimulating adventure of KRN 7000.

International audienceAssociated with the CD1d protein, KRN 7000, a potent synthetic α-galactosylceramide, is known to activate the invariant NKT immune cells. This stimulation then leads to the production of different cytokines modulating a T(H)1/T(H)2 immune response balance involved in protection against several pathologies such as autoimmune diseases and cancers. Various efforts have been made toward the synthesis of simple and more functionalized analogues in order to selectively induce T(H)1 or T(H)2-type cytokine production. Since the discovery of KRN 7000, structure-activity relationships, crystallographic and modelling studies have pointed to the potential of several GalCer analogues in term of selective bioactivity, and have highlighted interesting elements in order to better understand the recognition and activation mechanisms of immune iNKT cells. By presenting an up-to-date library of analogues, collecting recent breakthroughs done in crystallography and molecular modelling, and relating them to the available biological results, we hope that this review will highlight and help the scientific community in their KRN research