Metal clips induce folding of a short unstructured peptide into an alpha-helix via turn conformations in water. Kinetic versus thermodynamic products

Short peptides corresponding to two to four alpha-helical turns of proteins are not thermodynamically stable helices in water. Unstructured octapeptide Ac-His1-Ala2-Ala3-His4-His5-Glu6-Leu7-His8-NH(2) (1) reacts with two [Pd((15)NH(2)(CH(2))(2)(15)NH(2))(NO(3))(2)] in water to form a kinetically stable intermediate, [[Pden](2)[(1,4)(5,8)-peptide]](2), in which two 19-membered metallocyclic rings stabilize two peptide turns. Slow subsequent folding to a thermodynamically more stable two-turn alpha-helix drives the equilibrium to [[Pden](2)[(1,5)(4,8)-peptide]] (3), featuring two 22-membered rings. This transformation from unstructured peptide via turns to an alpha-helix suggests that metal clips might be useful probes for investigating peptide folding.     

Regioselective synthesis of antiparallel loops on a macrocyclic scaffold constrained by oxazoles and thiazoles

The regioselective syntheses and structures are reported for two tris-macrocylic compounds, each possessing two antiparallel loops on a macrocyclic scaffold constrained by two oxazoles and two thiazoles. NMR solution structures show the loops projecting from the same face of the macrocycle. Such molecules are shown to be prototypes for mimicking multiple loops of proteins.[structure: see text]     

Constraining Cyclic Peptides To Mimic Protein Structure Motifs

Many proteins exert their biological activities through small exposed surface regions called epitopes that are folded peptides of well‐defined three‐dimensional structures. Short synthetic peptide sequences corresponding to these bioactive protein surfaces do not form thermodynamically stable protein‐like structures in water. However, short peptides can be induced to fold into protein‐like bioactive conformations (strands, helices, turns) by cyclization, in conjunction with the use of other molecular constraints, that helps to fine‐tune three‐dimensional structure. Such constrained cyclic peptides can have protein‐like biological activities and potencies, enabling their uses as biological probes and leads to therapeutics, diagnostics and vaccines. This Review highlights examples of cyclic peptides that mimic three‐dimensional structures of strand, turn or helical segments of peptides and proteins, and identifies some additional restraints incorporated into natural product cyclic peptides and synthetic macrocyclic peptidomimetics that refine peptide structure and confer biological properties.     

First-order equations for gauge fields in spaces of dimension greater than four

We consider the possibility of satisfying the gauge field equations in dimensions greater than four by imposing linear relations amongst the components of the field strength tensor, F_μν, generalising the idea of self-duality in four dimensions.     

Deformations and renormalisations ofW ∞

Deformations of the infiniteN limit of the ZamolodchikovW _N algebra are discussed. A recent one, due to Pope, Romans and Shen with non-zero central extensions for every conformal spin is shown to be formally renormalisable to one representable in Moyal bracket form. Another deformation is discovered which, like the algebra of Pope et al. possesses automatic closure, but has non-zero central extension only in the Virasoro subalgebra.On Research Leave from the University of Durham UK; research supported in part by the Department of Energy under Grant DE[FG02/88/ER25065, and by a grant from the Alfred P. Sloan Foundation     

Vertex ring-indexed Lie algebras

Infinite-dimensional Lie algebras are introduced, which are only partially graded, and are specified by indices lying on cyclotomic rings. They may be thought of as generalizations of the Onsager algebra, but unlike it, or its sl(n) generalizations, they are not subalgebras of the loop algebras associated with sl(n). In a particular interesting case associated with sl(3), their indices lie on the Eisenstein integer triangular lattice, and these algebras are expected to underlie vertex operator combinations in CFT, brane physics, and graphite monolayers.     

Deformations of the canonical commutation relations

Deformations of the canonical commutation relations which have the effect of altering the spectrum of a standard Hamiltonian, bilinear in creation and annihilation operators are described. The problem of going over from an eigenvalue situation, as is the case in the vast majority of papers in the literature, to a theory with time evolution is discussed, and a special example with deformation parameter an Nth root of unity is constructed which possesses a consistent time evolution. This work is an account of some recent studies of associative deformations of the Heisenberg algebra of several creation and annihilation algebras, with Jean Nuyts of the University of Mons, Hainaut, together with some observations of my own concerning the difficulty of implementing time evolution in a quantum group context. It builds on earlier work with Cosmas Zachos (Argonne National Laboratory, USA), which in turn is re;ated to work of Manin, and Wess, Zumino and collaborators. The main idea is that, if quantum groups have any role in physics, then they must manifest themselves at the level of the basic rules of quantisation.     

Self-condensation of a thiazole-peptide bearing a 21-membered loop into a library of giant macrocycles with multiple orthogonal loops

[reaction: see text] Tetrapeptide analogue H-[Glu-Ser-Lys(Thz)]-OH, containing a turn-inducing thiazole constraint, was used as a template to produce a 21-membered structurally characterized loop by linking Glu and Lys side chains with a Val-Ile dipeptide. This template was oligomerized in one pot to a library (cyclo-[1](n)(), n = 2-10) of giant symmetrical macrocycles (up to 120-membered rings), fused to 2-10 appended loops that were carried intact through multiple oligomerization (chain extension) and cyclization (chain terminating) reactions of the template. A three-dimensional solution structure for cyclo-[1](3) shows all three appended loops projecting from the same face of the macrocycle. This is a promising approach to separating peptide motifs over large distances.     

Linkage isomerism in the binding of pentapeptide Ac-His(Ala)3His-NH2 to (ethylenediamine)palladium(II): effect of the binding mode on peptide conformation

The reaction of the pentapeptide Ac-His1-Ala2-Ala3-Ala4-His5-NH2 (AcHAAAHNH2) (1) with [Pd(en)(ONO2)2] (en = NH2CH2CH2NH2) in either DMF-d(7) or H2O:D2O (90%:10%) gave three linkage isomers of [Pd(en)(AcHAAAHNH2)](2+) (2), 2a, 2b, and 2c, which differ only in which pair of imidazole nitrogen atoms bind to Pd. In the most abundant isomer, 2a, Pd is bound by N1 from each of the two imidazole rings. In the minor isomers 2b and 2c, Pd is bound by N1(His1) and N3(His5) and by N3(His1) and N1(His5), respectively. The reactions of [Pd(en)(ONO2)2] with the N-methylated peptides Ac-(N3-MeHis)-Ala-Ala-Ala-(N3-MeHis)-NH2 (AcH*AAAH*NH2) (3), Ac-(N3-MeHis)-Ala-Ala-Ala-(N1-MeHis)-NH2 (AcH(*)AAAH(#)NH2) (4), and Ac-(N1-MeHis)-Ala-Ala-Ala-(N3-Me-His)-NH2 (AcH(#)AAAH(*)NH2) (5) each gave a single species [Pd(en)(peptide)](2+) in N,N-dimethylformamide (DMF) or aqueous solution, 7, 8, and 9, respectively, with Pd bound by the two nonmethylated imidazole nitrogen atoms in each case. These complexes were analogous to 2a, 2b, and 2c, respectively. Ac-(N1-MeHis)-Ala-Ala-Ala-(N1-MeHis)-NH2 (AcH(#)AAAH(#)NH2) (6) with [Pd(en)(ONO2)2] in DMF slowly gave a single product, [Pd(en)(AcH(#)AAAH(#)NH2)](2+) (10), in which Pd was bound by the N3 of each imidazole ring. The corresponding linkage isomer of 2 was not observed. Complex 10 was also the major product in aqueous solution, but other species were also present. All compounds were exhaustively characterized in solution by multinuclear 1D ((1)H , (13)C, and, with (15)N-labeled ethylenediamine, (15)N) and 2D (correlation spectroscopy, total correlation spectroscopy, transverse rotating-frame Overhauser effect spectroscopy (T-ROESY), heteronuclear multiple-bond correlation, and heteronuclear single quantum coherence) NMR spectra, circular dichroism (CD) spectra, electrospray mass spectroscopy, and reversed-phase high-performance liquid chromatography. ROESY spectra were used to calculate the structure of 2a, which contained a single turn of a peptide alpha helix in both DMF and water, the helix being better defined in DMF. The Pd(en)(2+) moiety was not used in structure calculations, but its location and coordination by one imidazole N1 from each histidine to form a 22-membered metallocycle were unambiguously established. Convergence of the structures was greatest when calculated with two hydrogen-bond constraints (Ala4 peptide NH...OC acetyl and His5 peptide NH...OC-His1) that were indicated by the low temperature dependence of these NH chemical shifts. Vicinal HN-CHalpha coupling constants and chemical shifts of alpha-H atoms were also consistent with a helical conformation. Similar long-range ROE correlations were observed for [Pd(en)(AcH(*)AAAH(*)NH2)](2+) (7), which displayed a CD spectrum in aqueous solution that suggested the presence of some helicity. Long-range ROE correlations were not observed for 8, 9, or 10, but a combination of NMR data and CD spectroscopy was interpreted in terms of the conformational behavior of the coordinated pentapeptide. Only for the linkage isomer [Pd(en)(AcH(*)AAAH(#)NH2)](2+) (8) was there evidence of a contribution from a helical conformation. The data for 8 were interpreted as interconversion between the helix and random coil conformations. Zn(2+) with peptides gave broad NMR peaks attributed to lability of this metal ion, while reactions of cis-[Pt(NH3)2(ONO2)2] were slow, giving a complex mixture of products rather than the macrochelate ring observed with Pd(en)(2+). In summary, these studies indicate that Pd(en)(2+) coordinates to histidine with similar preference for each of the two imidazole nitrogens, enabling the formation of up to four linkage isomers in its complexes with pentapeptides His-xxx-His. Only the N1-N1 linkage isomer that forms a 22-membered macrochelate ring is able to induce an alpha-helical peptide conformation, whereas the 20- and 21-membered rings of linkage isomers do not. This suggests that linkage isomeric mixtures may compromise histidine coordination to metal ions and reduce alpha-helicity.