Inherent Conformational Preferences of Ac‐Gln‐Gln‐NHBn: Sidechain Hydrogen Bonding Supports a β‐Turn in the Gas Phase

Gas‐phase single‐conformation spectroscopy is used to study Ac‐Gln‐Gln‐NHBn in order to probe the interplay between sidechain hydrogen bonding and backbone conformational preferences. This small, amide‐rich peptide offers many possibilities for backbone–backbone, sidechain–backbone, and sidechain–sidechain interactions. The major conformer observed experimentally features a type‐I β‐turn with a canonical 10‐membered ring C=O—H?N hydrogen bond between backbone amide groups. In addition, the C=O group of each Gln sidechain participates in a seven‐membered ring hydrogen bond with the backbone NH of the same residue. Thus, sidechain hydrogen‐bonding potential is satisfied in a manner that is consistent with and stabilizes the β‐turn secondary structure. This turn‐forming propensity may be relevant to pathogenic amyloid formation by polyglutamine segments in human proteins.     

Application of Privileged Molecular Framework of 7‐Fluoro‐1,4‐benzodiazepin‐2‐one‐5‐methylcarboxylate to the Synthesis of Its 1‐ and 5‐Disubstituted Analogs of Medicinal Interest

Synthetic potential of the privileged molecular framework of 7‐fluoro‐1,4‐benzodiazepin‐2‐one containing a methyl carboxylate substituent at its 5‐position was exploited to develop efficient protocols to the synthesis of several novel 5‐(1′,3′,4′)oxadiazole ring incorporated analogs of medicinal interest, appended with the Mannich's base motifs at the nitrogen atom in its seven‐membered ring.     

Synthesis of Cyclic Alkenylsiloxanes by Semihydrogenation: A Stereospecific Route to (Z)‐Alkenyl Polyenes

Cyclic alkenylsiloxanes were synthesized by semihydrogenation of alkynylsilanes—a reaction previously plagued by poor stereoselectivity. The silanes, which can be synthesized on multigram scale, undergo Hiyama–Denmark coupling to give (Z)‐alkenyl polyene motifs found in bioactive natural products. The ring size of the silane is crucial: five‐membered cyclic siloxanes also couple under fluoride‐free conditions, whilst their six‐membered homologues do not, enabling orthogonality within this structural motif.     

Host–Guest Interactions in ExBox4+

The host–guest interaction between poly aromatic hydrocarbon/azine and the newly synthesized ExBox⁴⁺ complex is studied with the help of density functional theory. The solvent‐phase interaction energy is found to decrease with gradual substitution of methine groups (?CH?) from the six‐membered ring of guest molecules with N atoms in the resultant azine@ExBox⁴⁺ complex. The nature of the binding interaction is studied with the help of newly developed noncovalent interaction (NCI) plot program package along with energy decomposition analysis and charge decomposition analysis. The interactions are mostly π‐type van der Waals interactions.     

Chondroitin Sulfate Tetrasaccharides: Synthesis,Three‐Dimensional Structure and Interaction with Midkine

The biological activity of midkine, a cytokine implicated in neuro‐ and tumourigenesis, is regulated by its binding to glycosaminoglycans (GAGs), such as heparin and chondroitin sulfate (CS). To better understand the molecular recognition of GAG sequences by this growth factor, the interactions between synthetic chondroitin sulfate‐like tetrasaccharides and midkine were studied by using different techniques. Firstly, a synthetic approach for the preparation of CS‐like oligosaccharides in the sequence GalNAc–GlcA was developed. A fluorescence polarisation competition assay was then employed to analyse the relative binding affinities of the synthetic compounds and revealed that midkine interacted with CS‐like tetrasaccharides in the micromolar range. The 3D structure of these tetramers was studied in detail by a combination of NMR spectroscopy experiments and molecular dynamics simulations. Saturation transfer difference (STD) NMR spectroscopy experiments indicate that the CS tetrasaccharides bind to midkine in an extended conformation, with similar saturation effects along the entire sugar chain. These results are compatible with docking studies that suggest an interaction of the tetrasaccharide with midkine in a folded structure. Overall, this study provides valuable information on the interaction between midkine and well‐defined, chemically synthesised CS oligosaccharides and these data can be useful for the design of more active compounds that modulate the biological function of this protein.     

Density functional theory calculation of cyclic carboxylic phosphorus mixed anhydrides as possible intermediates in biochemical reactions: Implications for the Pro‐Tide approach

Cyclic acyl phosphoramidates (CAPAs) are important components in several fundamental biological reactions such as protein synthesis and phosphorylation. These structures are particularly interesting in the nucleotide pro‐drug approach, Pro‐Tide, since they are putative intermediates in one of the hydrolysis steps required for activation. The central role played by the amino acid carboxylate function suggests first the formation of a cyclic mixed phosphorus anhydride, rapidly followed by water attack. To investigate such speculations, we performed quantum mechanical calculations using the B3LYP/6‐311+G** level of theory for the plausible mechanisms of action considered. In the five‐membered ring case, transition state theory demonstrated how the overall, gas‐phase, mechanism of action could be split into two in‐line addition–elimination (A–E) steps separated by a penta‐coordinate phosphorane intermediate. The difference between five‐membered and six‐membered ring first A–E was also explored, revealing a single step, unimolecular reaction for the six‐membered ring A–E profile. Implicit solvent contribution further confirmed the importance of CAPAs as reactive intermediates in such kind of reactions. Lastly, the second A–E pathway was analyzed to understand the complete pathway of the reaction. This analysis is the first attempt to clarify the putative mechanism of action involved in the activation of Pro‐Tides and casts light also on the possible mechanism of action involved in primordial protein syntheses, strengthening the hypothesis of a common cyclic mixed phosphorus anhydride species as a common intermediate. © 2012 Wiley Periodicals, Inc.     

Sensitive Detection of Small Molecule–Protein Interactions on a Metal–Insulator–Metal Label‐Free Biosensing Platform

The need to develop label‐free biosensing devices that enable rapid analyses of interactions between small molecules/peptides and proteins for post‐genomic studies has increased significantly. We report a simple metal–insulator–metal (MIM) geometry for fabricating a highly sensitive detection platform for biosensing. MIM substrates consisting of an Au–PMMA–Ag nanolayer were extensively studied using both theoretical and experimental approaches. By monitoring reflectivity changes at the normal incidence angle, we observed molecular interactions as the thickness of the biolayer increased on the substrate surface. These interactions included the adsorption of various proteins (Mw=6–150 kD) and interactions between small molecules (Mw≤2 kD) and the immobilized proteins. The interaction of designed monosaccharide‐modified designed peptides with various lectins was also clearly detected. These interactions could not be detected by the conventional Au‐only substrate. Thus, the MIM approach affords a powerful label‐free biosensing device that will aid our understanding of protein interactions and recognition.     

Density functional theory study of the interaction between formamide and uracil

The hydrogen bonding of complexes formed between the formamide and uracil molecule has been fully investigated in the present study using the density functional theory (DFT) method at varied basis set levels from 6‐31G to 6‐311++G(d,p). Eight stable cyclic structures with two hydrogen bonds involved in the interaction are found on the potential energy surface (PES). The four structures are seven‐membered rings; the others are eight‐membered rings. The eight‐membered ring is preferred over the seven‐membered one by analyzing the hydrogen bond lengths and the interaction energies. The infrared (IR) spectrum frequencies, IR intensities, and the vibrational frequency shifts are reported. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

Isomeric hexyl‐ketohydroperoxides formed by reactions of hexoxy and hexylperoxy radicals in oxygen

Isomerization reactions of peroxy radicals during oxidation of long‐chain hydrocarbons yield hydroperoxides, and therefore play an important role in combustion and atmospheric chemistry, because of their action as branching agents in these chain reaction processes. Different formation mechanisms and structures are involved. Three isomeric hexyl‐ketohydroperoxides are formed via isomerization reactions in oxygen of either hexoxy RO or hexylperoxy RO₂ radicals. In the temperature range 373–473 K, 2‐hexoxy (C₆H₁₃O) radical in O₂/N₂ mixtures gives 2‐hexanone‐5‐hydroperoxide via two consecutive isomerizations. The second one is a H transfer from a HC(OH) group occurring via a seven‐membered ring intermediate: Its rate constant has been determined at 453 and 483 K, and the general expression can be written as Hexylperoxy C₆H₁₃O₂ radical, present in n‐hexane oxidation by oxygen/nitrogen mixtures in the temperature range 543–573 K, gives 2‐hexanone‐4‐hydroperoxide, 3‐hexanone‐5‐hydroperoxide, and 2‐hexanone‐5‐hydroperoxide. The first two are formed through an isomerization reaction via a six‐membered ring intermediate, and the last through an isomerization reaction via a seven‐membered ring intermediate. The ratio of the rate constant of the isomerization reactions of RO₂ radicals via a seven‐membered ring intermediate to that via a six‐membered ring is found to be 0.795, and the rate constant expression via a seven‐membered ring intermediate is proposed: The role of these reactions in the formation of radicals in the troposphere is discussed. Other products arising in the reactional path, such as ketones, furans, and diketones, are identified. Identification of these ketohydroperoxides was made using gas chromatography/mass spectrometry with electron impact, and with NH₃ (or ND₃) chemical ionization. © 2003 Wiley Periodicals, Inc. Int J Chem Kinet 35: 354–366, 2003     

Total Synthesis of Talatisamine

Talatisamine ( 1 ) is a member of the C₁₉‐diterpenoid alkaloid family, and exhibits K⁺ channel inhibitory and antiarrhythmic activities. The formidable synthetic challenge that 1 presents is due to its highly oxidized and intricately fused hexacyclic 6/7/5/6/6/5‐membered‐ring structure (ABCDEF‐ring) with 12 contiguous stereocenters. Here we report an efficient synthetic route to 1 by the assembly of two structurally simple fragments, chiral 6/6‐membered AE‐ring 7 and aromatic 6‐membered D‐ring 6 . AE‐ring 7 was constructed from 2‐cyclohexenone ( 8 ) through fusing an N‐ethylpiperidine ring by a double Mannich reaction. After coupling 6 with 7 , an oxidative dearomatization/Diels–Alder reaction sequence generated fused pentacycle 4 b . The newly formed 6/6‐membered ring system was then stereospecifically reorganized into the 7/5‐membered BC‐ring of 3 via a Wagner–Meerwein rearrangement. Finally, Hg(OAc)₂ induced an oxidative aza‐Prins cyclization of 2 , thereby forging the remaining 5‐membered F‐ring. The total synthesis of 1 was thus accomplished by optimizing and orchestrating 33 transformations from 8 .     

Singly and Doubly 1,2‐Phenylene‐Inserted Porphyrin Arch‐Tape Dimers: Synthesis and Highly Contorted Structures

Singly and doubly 1,2‐phenylene‐inserted Ni^II porphyrin arch‐tape dimers 3 and 9 were synthesized from the corresponding β‐to‐β 1,2‐phenylene‐bridged Ni^II porphyrin dimers 5 and 11 via Ni⁰‐mediated reductive cyclization and DDQ/Sc(OTf)₃‐promoted oxidative cyclization as key steps, respectively. Owing to the fused eight‐membered ring(s), 3 showed a more contorted structure than those of previously reported arch‐tape dimers 2 a and 2 b possessing a fused seven‐membered ring. Furthermore, 9 displayed much larger molecular contortion. As the molecular contortion increases, the Q band of the absorption spectrum becomes more red‐shifted and the electrochemcial HOMO–LUMO gap becomes smaller, reaching at 1294 nm and 0.77 eV in 9 , respectively. The effect of molecular contortion on the electronic properties was studied by means of DFT calculations.     

Stereoelectronic Model To Explain Highly Stereoselective Reactions of Seven‐Membered‐Ring Oxocarbenium‐Ion Intermediates

Nucleophilic attack on seven‐membered‐ring oxocarbenium ions is generally highly stereoselective. The preferred mode of nucleophilic attack forms the product in a conformation that minimizes transannular interactions, thus leading to different stereoselectivity as compared to that of reactions involving six‐membered‐ring oxocarbenium ions.     

Thermodynamic basis for promiscuity and selectivity in protein-protein interactions: PDZ domains, a case study

Like other protein-protein interaction domains, PDZ domains are involved in many key cellular processes. These processes often require that specific multiprotein complexes be assembled, a task that PDZ domains accomplish by binding to specific peptide motifs in target proteins. However, a growing number of experimental studies show that PDZ domains (like other protein-protein interaction domains) can engage in a variety of interactions and bind distinct peptide motifs. Such promiscuity in ligand recognition raises intriguing questions about the molecular and thermodynamic mechanisms that can sustain it. To identify possible sources of promiscuity and selectivity underlying PDZ domain interactions, we performed molecular dynamics simulations of 20 to 25 ns on a set of 12 different PDZ domain complexes (for the proteins PSD-95, Syntenin, Erbin, GRIP, NHERF, Inad, Dishevelled, and Shank). The electrostatic, nonpolar, and configurational entropy binding contributions were evaluated using the MM/PBSA method combined with a quasi-harmonic analysis. The results revealed that PDZ domain interactions are characterized by overwhelmingly favorable nonpolar contributions and almost negligible electrostatic components, a mix that may readily sustain promiscuity. In addition, despite the structural similarity in fold and in recognition modes, the entropic and other dynamical aspects of binding were remarkably variable not only across PDZ domains but also for the same PDZ domain bound to distinct ligands. This variability suggests that entropic and dynamical components can play a role in determining selectivity either of PDZ domain interactions with peptide ligands or of PDZ domain complexes with downstream effectors.     

Two isomeric 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]hexahydro­isoindole‐1,3‐dione compounds

The molecular structures of 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]‐1,3,4,5,6,7‐hexahydro­isoindole‐1,3‐dione, C₁₇H₁₃ClFNO₃, (I), and the isomeric compound 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]‐cis‐1,3,3a,4,7,7a‐hexahydro­isoindole‐1,3‐dione, (II), are, as anticipated, significantly different in their conformations and in the distances between the farthest two atoms. The six‐membered ring of the 1,3,4,5,6,7‐hexahydro­isoindole‐1,3‐dione moiety in (I) adopts a half‐chair conformation. The dihedral angle between the five‐membered dione ring of (I) and the benzene ring is 50.96 (7)°. The six‐membered ring of the cis‐1,3,3a,4,7,7a‐hexahydro­isoindole‐1,3‐dione moiety in (II) adopts a boat conformation. The dihedral angle in (II) between the five‐membered dione ring and the benzene ring is 61.03 (13)°. In the crystal structures, the molecules are linked by C—H⋯O hydrogen bonds and weak π–π interactions. Compound (I) is a much more potent herbicide than (II). The Cl⋯H distances between the farthest two atoms in (I) and (II) are 11.37 and 9.97 Å, respectively.     

Exploiting Multivalent Nanoparticles for the Supramolecular Functionalization of Graphene with a Nonplanar Recognition Motif

The supramolecular modification of planar graphene with the geometrically mismatched, curved 9,10‐di(1,3‐dithiole‐2‐ylidene)‐9,10‐dihydroanthracene (exTTF) molecule is demonstrated. The exTTF–graphene interaction is governed by π–π and CH–π interactions, with a negligible contribution from charge transfer. We amplified these weak forces through multivalent gold nanoparticles. Our results show that planarity is not a prerequisite for recognition motifs for graphene.     

Theoretical analyses of the host–guest interaction within chlorine hydrate

The host–guest interaction is necessary for the stabilization of hydrates. Using Density Function Theory methods, the host–guest interaction within an unconventional chlorine hydrate was investigated, in combination with typical noncovalent analyses. The host–guest interaction energy was predicted to be as high as 17.51 kcal/mol, which was stronger than the typical van der Waals (vdW) interaction, due to an involvement of up to 20 Cl…O interactions. Polarization and dispersion energies made up the main contribution to the total interaction energy. Further visualization of the host–guest interaction validated, together with the general Cl…O interaction, another vdW interaction between the guest‐Cl atom and the five‐membered H₂O cluster. Isosurfaces associated with two patterns of vdW interactions yielded a better “fit” in shape, suggesting their cooperativity in stabilizing the steric configuration. The σ‐region on the guest‐Cl atom was verified to regulate the electron redistribution over the molecular space. These results are useful for understanding specific halogen behavior, and the origin and nature of host–guest interaction in hydrates. © 2013 Wiley Periodicals, Inc.     

计算机模拟内毒素吸附剂吸附机理的研究

应用计算机模拟的方法研究了内毒素吸附剂的吸附机理. 模拟结果显示, 以二甲胺为配体的吸附剂, 当β位存在羟基时, 此羟基可与内毒素分子间形成氢键, 并形成一个八元环的稳定结构. 此时吸附剂与内毒素之间存在静电、 氢键、 疏水相互作用和八元环的协同作用. 同时模拟了羟基位于配体不同位置的吸附剂与内毒素的相互作用. 结果表明, 静电作用为主要的相互作用力, 羟基的位置对吸附剂的吸附能力影响显著.     

Polyaddition of bis(seven‐membered cyclic carbonate) with diamines: A novel and efficient synthetic method for polyhydroxyurethanes

This article deals with the polyaddition of a novel bis(seven‐membered cyclic carbonate), 1,2‐bis[3‐(1,3‐dioxepan‐2‐one‐5‐yl)‐propylthio]ethane, with the diamines 4,9‐dioxa‐1,12‐dodecanediamine and p‐xylylenediamine. The polyaddition was carried out at 30–70 °C for 6–24 h in dimethyl sulfoxide to obtain the corresponding polyhydroxyurethanes with number‐average molecular weights of 10,900–35,700 in good yields. The reaction of a monofunctional seven‐membered cyclic carbonate, 5‐allyl‐1,3‐dioxepan‐2‐one (7CC), with monoamines was also carried out to examine the reactivity in comparison with that of six‐ and five‐membered cyclic carbonates. The reaction rate constants of 7CC with n‐hexylamine and benzylamine were estimated to be 48.5 and 11.0 L/mol · h, respectively, in dimethyl sulfoxide‐d₆ (initial reagent concentration = 1 M) at 30 °C. The seven‐membered cyclic carbonate ring was 2.98 and 5.82 kcal/mol more strained than those of the six‐ and five‐membered cyclic carbonates, respectively, according to a semiempirical molecular orbital calculation with the PM3 Hamiltonian. © 2001 John Wiley & Sons, Inc. J Polym Sci Part A: Polym Chem 39: 4091–4100, 2001     

Cyclomicrobuxine monohydrate

In the title compound, 3β‐(dimethylamino)‐16α‐hydroxy‐14‐methyl‐4‐methylene‐9,19‐cyclo‐5α‐pregnan‐20‐one monohydrate, C₂₅H₃₉NO₂·H₂O, the pentacyclo steroidal alkaloid is composed of three six‐membered, one five‐membered and one three‐membered ring. The molecular dimensions are as expected. The structure is stabilized by hydrogen bonds involving H and O atoms of water and the alkaloid molecules, with strong N?O [2.829 (7) Å] and O?O [2.790 (6) and 2.949 (7) Å] interactions.