Amyloid formation from an α-helix peptide bundle is seeded by 3(10)-helix aggregates

Transformation of proteins and peptides to fibrillar aggregates rich in β sheets underlies many diseases, but mechanistic details of these structural transitions are poorly understood. To simulate aggregation, four equivalents of a water‐soluble, α‐helical (65 %) amphipathic peptide (AEQLLQEAEQLLQEL) were assembled in parallel on an oxazole‐containing macrocyclic scaffold. The resulting 4α‐helix bundle is monomeric and even more α helical (85 %), but it is also unstable at pH 4 and undergoes concentration‐dependent conversion to β‐sheet aggregates and amyloid fibrils. Fibrils twist and grow with time, remaining flexible like rope (>1 μm long, 5–50 nm wide) with multiple strings (2 nm), before ageing to matted fibers. At pH 7 the fibrils revert back to soluble monomeric 4α‐helix bundles. During α→β folding we were able to detect soluble 3₁₀ helices in solution by using 2D‐NMR, CD and FTIR spectroscopy. This intermediate satisfies the need for peptide elongation, from the compressed α helix to the fully extended β strand/sheet, and is driven here by 3₁₀‐helix aggregation triggered in this case by template‐promoted helical bundling and by hydrogen‐bonding glutamic acid side chains. A mechanism involving α?α₄?(3₁₀)₄?(3₁₀)_n?(β)_n?m(β)_n equilibria is plausible for this peptide and also for peptides lacking hydrogen‐bonding side chains, with unfavourable equilibria slowing the α→β conversion.     

Carbon-carbon bond formation by radical addition of α-trifluoromethylacrylate with cyclic ethers

The radical addition reactivity of tert-butyl α-trifluoromethylacrylate (CH₂C(CF₃)COOC(CH₃)₃) (BFMA) with cyclic ethers was investigated in order to compare to that of perfluoroisopropenyl ester. One to one addition compound of BFMA with tetrahydrofuran (THF) was produced in fairy high yields in the presence of 2,2′-azobisisobutyronitrile, benzoyl peroxide or di-tert-butyl peroxide to give 2-substituted THF derivative. Time-conversion investigation showed much higher reactivity of BFMA compared to that of 2-benzoxypentafluoropropene [CF₂C(CF₃)OCOC₆H₅]. Radical additions of BFMA with 1,4-dioxane, 1,3-dioxolane and tetrahydropyran were also examined to afford corresponding 1:1 addition products in fairly high yields by achieving carbon-carbon bond formation. It is then concluded that no interconversion of fluoroalkylcarbon radical and hydrocarbon radical may take place in the reaction system of BFMA which possesses two less fluorines in the vinyl group compared to 2-benzoxypentafluoropropene. The method may be a facile way to prepare trifluoromethyl-substituted organic compounds accompanied by the formation of carbon-carbon bonds by the aid of fluorine atoms.     

Where gold meets a hydrogen bond?

This is a short survey of the area of the hydrogen bonding where the noble and coinage metal gold enters its manifold of the proton acceptors. It is largely focused on the nonconventional hydrogen bonds that are formed in the complexes of the auride anion Au⁻ with HF, (HF)₂, H₂O, (H₂O)₂, NH₃, and (NH₃)₂, as mostly experimentally investigated to date. A thorough comparison of the experimental and computational data on these nonconventional hydrogen bonds is the main motif of the present work.     

Promoting peptide α-helix formation with dynamic covalent oxime side-chain cross-links

Covalent side-chain cross-linking has been shown to be a viable strategy to control peptide folding. We report here that an oxime side-chain linkage can elicit α-helical folds from peptides in aqueous solution. The bio-orthogonal bridge is formed rapidly under neutral buffered conditions, and the resulting cyclic oximes are capable of dynamic covalent exchange.     

Translocation of α-helix chains through a nanopore

The translocation of α-helix chains through a nanopore is studied through Langevin dynamics simulations. The α-helix chains exhibit several different characteristics about their average translocation times and the α-helix structures when they transport through the nanopores under the driving forces. First, the relationship between average translocation times τ and the chain length N satisfies the scaling law, τ～N(α), and the scaling exponent α depends on the driving force f for the small forces while it is close to the Flory exponent (ν) in the other force regions. For the chains with given chain lengths, it is observed that the dependence of the average translocation times can be expressed as τ～f(-1/2) for the small forces while can be described as τ～f in the large force regions. Second, for the large driving force, the average number of α-helix structures N(h) decreases first and then increases in the translocation process. The average waiting time of each bead, especially of the first bead, is also dependent on the driving forces. Furthermore, an elasticity spring model is presented to reasonably explain the change of the α-helix number during the translocation and its elasticity can be locally damaged by the large driving forces. Our results demonstrate the unique behaviors of α-helix chains transporting through the pores, which can enrich our insights into and knowledge on biopolymers transporting through membranes.     

Amphiphilic α-helix mimetics based on a benzoylurea scaffold

The design and synthesis of amphiphilic benzoylurea α-helix mimetics is described. These conformationally constrained molecules allow for the correct angular and spatial projection of hydrophobic and hydrophilic groups and thus the reproduction of side-chains on both faces of an α-helix.     

Constrained α/γ-peptides: a new stable extended structure in solution without any hydrogen bond and characterized by a four-fold symmetry

Small α/γ-peptides alternating α-aminoisobutyric acid and cyclic γ-amino acid residues are described. NMR studies together with restrained simulated annealing revealed that an extended backbone conformation largely dominates in solution for as short as 4-residues long oligomers. This new fold type is devoid of any hydrogen bond and characterized by a four-fold symmetry.     

Reaction of diphenylphosphine oxide with a 10-methylacridinium salt. Reversible formation of a P?C covalent bond

Diphenylphosphine oxide ( 1 ′) reacts reversibly with a 10-methylacridinium salt ( 2 ) in acetonitrile at 20°C to equilibrate with a new salt 3 formed by the addition of 1 ′ to the cation of 2 . The forward reaction in this equilibrium proceeds via nucleophilic attack by the phosphorus atom of diphenylphosphinous acid ( 1 ), the trivalent tautomer of 1 ′, upon the 9-carbon atom of the cation of 2 , forming a phosphorus–carbon covalent bond. The equilibrium constant has been determined by UV-vis and ¹H NMR spectroscopy as well as by HPLC analysis. The reaction has been analyzed kinetically, and the results have been compared with those obtained in the similar reaction of an alkyl ester of 1 , the diphenylphosphinite ( 5 ), with 2 that gives the phosphonium salt 6 . It is suggested that 6 is much more stable than 3 . The equilibrium constant for the tautomerism between 1 ′ and 1 has also been estimated. © 1995 John Wiley & Sons, Inc.     

Enantioselective hydrogen atom transfer to α-sulfonyl radicals controlled by selective coordination of a chiral Lewis acid to an enantiotopic sulfonyl oxygen

Enantioselective hydrogen atom transfer to α-sulfonyl radicals generated from the alkyl radical addition to 2-propenyl and 1-phenylethenyl sulfones in the presence of chiral Lewis acids affords products with high enantioselectivity. The stereochemical course is discussed with the transition states involving selective coordination of a chiral Lewis acid to an enantiotopic sulfonyl oxygen.     

Enhancement of α-helix mimicry by an α/β-peptide foldamer via incorporation of a dense ionic side-chain array

We report a new method for preorganization of α/β-peptide helices, based on the use of a dense array of acidic and basic side chains. Previously we have used cyclically constrained β residues to promote α/β-peptide helicity; here we show that an engineered ion pair array can be comparably effective, as indicated by mimicry of the CHR domain of HIV protein gp41. The new design is effective in biochemical and cell-based infectivity assays; however, the resulting α/β-peptide is susceptible to proteolysis. This susceptibility was addressed via introduction of a few cyclic β residues near the cleavage site, to produce the most stable, effective α/β-peptide gp41 CHR analogue identified. Crystal structures of an α- and α/β-peptide (each involved in a gp41-mimetic helix bundle) that contain the dense acid/base residue array manifest disorder in the ionic side chains, but there is little side-chain disorder in analogous α- and α/β-peptide structures with a sparser ionic side-chain array. These observations suggest that dense arrays of complementary acidic and basic residues can provide conformational stabilization via Coulombic attractions that do not require entropically costly ordering of side chains.     

Iridium pentahydride complex catalyzed formation of CC bond by CH bond activation followed by olefin insertion

The formation of carbon-carbon bond was found to occur by first carbon-hydrogen bond activation followed by olefin insertion under the catalysis of an iridium pentahydride complex.     

New electrophilic addition of α-diazoesters with ketones for enantioselective C-N bond formation

α-Diazoesters were discovered to be good electrophiles in a catalytic asymmetric α-functionalization of ketones for the first time. This reaction also provided a direct and efficient method for C-N bond formation with excellent yields (up to 98%) and enantioselectivities (up to 99% ee) under mild conditions. The application of the electrophilicity of α-diazoesters opens up a novel way to access the diversity of diazo chemistry.     

When does a hydrogen bond become a van der Waals interaction? a topological answer

The hydrogen bond (H-bond) is among the most important noncovalent interaction (NCI) for bioorganic compounds. However, no “energy border” has yet been identified to distinguish it from van der Waals (vdW) interaction. Thus, classifying NCIs and interpreting their physical and chemical importance remain open to great subjectivity. In this work, the “energy border” between vdW and H-bonding interactions was identified using a dimer of water, as well as for a series of classical and nonclassical H-bonding systems. Through means of the quantum theory of atoms in molecules and in particular the source function, it was possible to clearly identify the transition from H-bonding to vdW bonding via analysis of the electronic structure. This “energy border” was identified both on elongating the interatomic interaction and by varying the contact angle. Hence, this study also redefines the “critic angle” previously proposed by Galvão et al. (J. Phys. Chem. A 2013, 117, 12668). Consequently, such “energy border” through an analysis of atomic basins volume variation was possible to identify the end of long-range interactions. © 2019 Wiley Periodicals, Inc.     

Hydrogen bond surrogate stabilized water soluble 310-helix from a disordered pentapeptide containing coded α-amino acids

Replacing a hypothetical i?+?3?→?i peptide H-bond in a disordered pentapeptide, that lacks any helicogenic C^α-tetrasubstituted residues, with a propyl linker and carbamylating the N-terminal nitrogen constrains it in the elusive 3₁₀-helical structure with high helicity and stability under varying conditions of temperature and pH, confirmed by NMR and CD analyses.     

Novel carboncarbon bond formation induced by depalladation of organometallic compounds

Two internal alkynes undergo insertion at 20°C into the PdC bond of the cyclopalladated derivative of dimethylaminomethylferrocene to give new organometallic compounds. When the reaction with diphenylacetylene is performed at higher temperatures, depalladation occurs readily to give six- and seven-membered ortho-fused rings through new annulation reactions of phenyl groups, formation of one of these involving also the cleavage of a CN bond.     

Supramolecular dimer formation through hydrogen bond extensions of carboxylate ligands – Path for magnetic exchange

A new complex of unusual composition [Cu(3-O₂Nbz)₂(nia)(H₂O)₂] (1) (nia = nicotinamide, 3-O₂Nbz = 3-nitrobenzoate) has been prepared and studied together with two other complexes of composition [Cu(4-O₂Nbz)₂(nia)₂(H₂O)₂] (2) and [Cu(4-O₂Nbz)₂(nia)₂]?(4-O₂NbzH)₂ (3) (4-O₂Nbz = 4-nitrobenzoate). The composition of all complexes has been determined by elemental analysis, the complexes have been studied by electronic, infrared and EPR spectroscopy, as well as by magnetization measurements over the temperature range 1.8–300 K, and their structures have been solved. The structure of complex (1) consists of molecules, where Cu(II) atom is monodentately coordinated by the pair of 3-nitrobenzoato anions in trans  -positions together with water and nicotinamide molecules, forming nearly tetragonal basal plane, and by another water molecule in axial position of tetragonal-pyramidal coordination polyhedron. The neighboring molecule coordination polyhedron basal planes are coplanar and allow formation of supramolecular dimers with strong H-bonds between hydrogen atoms from equatorially coordinated water molecules and uncoordinated carboxylate oxygen atoms thus giving the nearest Cu?$?$Cu distance of 4.886(2) Å. Magnetization measurements showed that complex (1) exhibits maximum of magnetic susceptibility at 6.5 K and a fit to Bleaney-Bowers equation gave singlet–triplet energy gap 2J = −6.25 cm⁻¹, and zJ′ = −0.03 cm⁻¹. This might be an experimental proof that the carboxylate bridges extended with hydrogen bonds are the pathway of the spin–spin interactions. The temperature dependence of changes in EPR spectra of (1) and the spectrum at 4.2 K have confirmed its hydrogen bonded dimeric structure. The calculated Cu?$?$Cu distance 4.8 Å is in very good agreement with the value obtained from crystal structure. The complexes (2) and (3) at 300 K exhibit magnetic moment μ_eff = 1.98 B.M. and μ_eff = 1.84 B.M., respectively. These values practically do not change with lowering the temperature up to 5 K and only small drops to μ_eff = 1.87 B.M. (for (2)) and μ_eff = 1.79 B.M. (for (3)) at 1.8 K have been observed. The EPR spectra of complex (2) at room temperature as well as at 77 K are of axial type with g_⊥ = 2.062 and g_|| = 2.285 and exhibit resolved parallel hyperfine splitting with A_|| = 160 Gauss. The EPR spectra of complex (3) at room temperature as well as at 77 K are of axial type with g_⊥ = 2.065 and g_|| = 2.235 and exhibit unresolved parallel hyperfine splitting. EPR spectra of (2) and (3) are consistent with the X-ray structure.     

Using thioamides to site-specifically interrogate the dynamics of hydrogen bond formation in β-sheet folding

Thioamides are sterically almost identical to their oxoamide counterparts, but they are weaker hydrogen bond acceptors. Therefore, thioamide amino acids are excellent candidates for perturbing the energetics of backbone-backbone H-bonds in proteins and hence should be useful in elucidating protein folding mechanisms in a site-specific manner. Herein, we validate this approach by applying it to probe the dynamic role of interstrand H-bond formation in the folding kinetics of a well-studied β-hairpin, tryptophan zipper. Our results show that reducing the strength of the peptide's backbone-backbone H-bonds, except the one directly next to the β-turn, does not change the folding rate, suggesting that most native interstrand H-bonds in β-hairpins are formed only after the folding transition state.