Conformational Behavior of β-Proline Oligomers

Sandvoss, Leah M.; Carlson, Heather A.

doi:10.1021/ja036471d

Cited by 34 publications

(34 citation statements)

References 40 publications

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“…Like the present (T4) n structures for oligomers of 9 , calculations for the tetramer of 7 predict ψ = 65° to be slightly favored 7. Calculations for oligomers 5 predict (C1) n conformations to be favored 4. Noteably, the (C1) 4 and (T4) 4 oligomers under discussion do have alternating anti orientations for their carbonyl dipoles in common.…”

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confidence: 54%

Oligomers of a 5-Carboxy-methanopyrrolidine β-Amino Acid. A Search for Order

et al. 2010

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CD spectra for homooligomers (n = 4,6,8) of (1S,4R,5R)-5-syn-carboxy-2-azabicyclo[2.1.1]hexane (MPCA), a methano-bridged pyrrolidine β-carboxylic acid, suggest an ordered secondary structure. Even in the absence of internal hydrogen bonding, solution NMR, Xray, and in silico analyses of the tetramer are indicative of conformations with trans amides and C 5 -amide-carbonyls oriented toward the C 4 bridgehead. This highly constrained β-amino acid could prove useful in the on-going development of well-defined foldamers.Among naturally occurring α-aminoacids proline 1 is the only secondary amine. Although this means that homooligomers of proline do not have N-H protons available to stabilize secondary structures by hydrogen bond, polyproline still forms ordered oligomers.1 In the course of the rational design of β-peptides related to natural peptides, Seebach2 wondered if β-peptidic chains without backbone H-bonds might also fold into stable secondary structures. To explore this possibility Seebach and coworkers prepared two methylene homologs of proline by formal insertion of a methylene either between the carbonyl C-atom and the C(α)-atom to give 2 or between the C(α) and C(β)-atoms to give 3. Oligomers (n = 3,6,12,18) of (R)-2 with terminal N-Boc and OBn groups all gave CD patterns in methanol with an intense minimum at 202 nm and a maximum at 223 that seemed indicative of order. The absolute mean-residue molar ellipticity at both 202 and 223 nm decreases with growing chain length suggesting that the secondary structure of longer peptide chains from 2 is destabilized. Similarly the CD spectra of oligomers (n = 3,6) of all (S)-3 with terminal NBoc and OEt groups in methanol also gave some indications of secondary structure. The mean residue molar ellipticity of the hexamer at 230 nm is nearly three times larger than the trimer indicating that in this case the secondary structure may be stabilized by the longer β-peptide chain. Gellman4 independently investigated oligomers (n = 2-6) of all (S)-3 with terminal N-Boc and OBn groups in methanol and observed a maximum ellipticity at 228 nm when n = 3-6. However, little evidence beyond CD spectra was provided to show that these β-amino acid oligomers adopted well-defined structures in solution.A model was proposed for the oligomeric peptides of 2.2 It assumed an all-trans amide structure with a Φ angle of −72° enforced by the pyrrolidine ring. An antiperiplanar conformation around the C(α)-C(β) bond (θ = 180°) was chosen on the basis of this angle in a trifluoroacetate salt of a trimer of 2 that contains amine and benzyl ester end groups. However, it should be noted that the peptide salt crystallized with four CF 3 COOH molecules and the carbonyls of the amide bonds of the salt were hydrogen bonded to acid molecules. A large angle ψ = 180° was chosen so that the large substituents at C(α) were antiperiplanar to the large substituents at the carbonyl C-atom. The outcome of this somewhat speculative model is a right-handed 10 3 helix with three pitches to bring re...

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supporting

confidence: 54%

Oligomers of a 5-Carboxy-methanopyrrolidine β-Amino Acid. A Search for Order

et al. 2010

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“…In parallel with and independently of our investigations into simple, open-chain bpeptides consisting of homologated proteinogenic amino acids, oligomers consisting of cyclic b-amino acid residues have been studied by Gellman and his group at the University of Wisconsin in Madison [255] [266] (see the (R,R)-2-aminocyclohexane-(ACHC) and (R,R)-2-aminocyclopentanecarboxylic acid (ACPC), and their associ- [443]. Oligomers of cis-aminooxetanecarboxylic acid (derived from a 3-amino-6-deoxy-hexose) form an (M)-10-helix (with 10-membered H-bonded rings) [445a]; the analogous ciscyclobutane derivative folds to a turn with a 14-membered H-bonded ring [445b].…”

Section: B-peptides Made Of Carbocyclic and Heterocyclic Aminocarboxymentioning

confidence: 99%

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Seebàch

Beck

Bierbaum

2004

Chemistry & Biodiversity

923

562

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The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as ...

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“…Computational studies of foldamers are still in their infancy. Several groups have used simulation approaches to study the conformational space available to peptidomimetics incorporating D-amino acids 104, 105 or β-amino acids 106, 107 , as well as completely non-biological foldamers such as m -phenylene ethylenes (mPE) 108 . These studies establish non-natural scaffolds which can then be functionalized to facilitate reactivity.…”

Section: Catalytic Foldamersmentioning

confidence: 99%

Designing artificial enzymes by intuition and computation

2009

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The rational design of artificial enzymes either by applying physio-chemical intuition of protein structure and function or with the aid of computation methods is a promising area of research with the potential to tremendously impact medicine, industrial chemistry and energy production. Designed proteins also provide a powerful platform for dissecting enzyme mechanisms of natural systems. Artificial enzymes have come a long way, from simple α-helical peptide catalysts to proteins that facilitate multi-step chemical reactions designed by state-of-the-art computational methods. Looking forward, we examine strategies employed by natural enzymes which could be used to improve the speed and selectivity of artificial catalysts.

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Conformational Behavior of β-Proline Oligomers

Cited by 34 publications

References 40 publications

Oligomers of a 5-Carboxy-methanopyrrolidine β-Amino Acid. A Search for Order

Oligomers of a 5-Carboxy-methanopyrrolidine β-Amino Acid. A Search for Order

The World of β‐ and γ‐Peptides Comprised of Homologated Proteinogenic Amino Acids and Other Components

Designing artificial enzymes by intuition and computation

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