External Chirality-Triggered Helicity Control Promoted by Introducing a β-Ala Residue into the N-Terminus of Chiral Peptides

Graduate School of Engineering, Nagoya Institute of Technology, Nagoya, Aichi, Japan
Biomacromolecules (Impact Factor: 5.75). 07/2004; 5(4):1231-40. DOI: 10.1021/bm0344001
Source: PubMed


The noncovalent chiral domino effect (NCDE), defined as chiral interaction upon an N-terminus of a 3(10)-helical peptide, will provide a unique method for structural control of a peptide helix through the use of external chirality. On the other hand, the NCDE has not been considered to be effective for the helicity control of peptides strongly favoring a one-handed screw sense. We here aim to promote the NCDE on peptide helicity using two types of nonapeptides: H-beta-Ala-Delta(Z)Phe-Aib-Delta(Z)Phe-X-(Delta(Z)Phe-Aib)(2)-OCH(3) [Delta(Z)Phe = alpha,beta-didehydrophenylalanine, Aib = alpha-aminoisobutyric acid], where X as the single chirality is L-leucine (1) or L-phenylalanine (2). NMR, IR, and CD spectroscopy as well as energy calculation revealed that both peptides alone form a right-handed 3(10)-helix. The original CD amplitudes or signs in chloroform, irrespective of a strong screw-sense preference in the central chirality, responded sensitively to external chiral information. Namely added Boc-L-amino acid stabilized the original right-handed helix, while the corresponding d-isomer destabilized it or transformed it into a left-handed helix. These peptides were also shown to bind more favorably to an L-isomer from the racemate. Although similar helicity control was observed for analogous nonapeptides bearing an N-terminal Aib residue (Inai, Y.; et al. Biomacromolecules 2003, 4, 122), the present findings demonstrate that the N-terminal replacement by the beta-Ala residue significantly improves the previous NCDE to achieve more effective control of helicity. Semiempirical molecular orbital calculations on complexation of peptide 2 with Boc-(L or D)-Pro-OH reasonably explained the unique conformational change induced by external chirality.

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    ABSTRACT: Complex structure and its energy were theoretically predicted between the N-terminal segment of right-handed 310-helical peptide (1) and chiral acid based on various amino acids. Two categories of the chiral acids have been chosen. One is N-carbonyl-blocked amino acid for the three-point coordination to the N-terminal sequence of peptide 1. The other acid for the two-point coordination contains no extra carbonyl groups. Energy minimization from the corresponding initial models was performed by semiempirical molecular orbital calculation. In each amino acid species, the three-point coordination, compared with the two-point type, tends to generate larger difference in energies of D-/L-complexes, which are more stable for L-species bound to right-handed helix. In the three-point binding, N-carbonyl-blocked L-amino acid is prone to adopt negative φ values. Density functional method was also applied to smaller analogs, providing similar tendency in complex structure and energy difference. The predictions obtained here are fully consistent with our previous findings [Y. Inai et al., J. Am. Chem. Soc., 125, 8151–8162 (2003)], in which preferential induction of right-handed helix in peptide 1 occurs with N-carbonyl-protected L-amino acid, but inefficiently with simple carboxylic acid. The energetic advantage for the three-point binding implies the function of 310-helical N-terminus to discriminate the chirality of N-carbonyl-blocked peptide acid molecule.Keywords: Chiral Discrimination, 310-Helix, N-Terminus, Three-point Interaction, Molecular Orbital Calculation, Chirality of Amino Acid, Helix Sense
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    ABSTRACT: Electronic circular dichroism (CD) spectra as well as transitions from ground to excited states were predicted for a helical nonapeptide based on alternative sequence--[Z-alpha,beta-dehydrophenylalanine (Delta(Z)Phe)-X]--through semiempirical molecular orbital computation combined with time-dependent (TD) method. The simulation was performed for its various conformers that differ in helix type, helix sense, and Delta(Z)Phe side-chain orientation. These conformational variations have been shown to depend largely on its CD spectra. Comparison between simulated and observed CD profiles reveals that peptide 1 in solution favors a right-handed 3(10)-helix that adopts phenyl (Delta(Z)Phe) planes basically in a vertical orientation with respect to the helix axis. These predictions were essentially supported from CD simulation of a shorter helical analogue at ab inito or density functional TD levels. The theoretical CD-conformation relationship should provide us useful guideline for determination of helix sense in the dehydropeptide, and for estimation of its conformations statistically averaged in solution.
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    ABSTRACT: Noncovalent chiral domino effect (NCDE) has been proposed as terminal-specific interaction upon a 310-helical peptide chain, of which the helix sense is manipulated by an external chiral stimulus (mainly amino acid derivatives) operating on the N-terminus (Inai, Y., et al. J Am Chem Soc 2000, 122, 11731–11732; ibid., 2002, 124, 2466–2473; ibid., 2003, 125, 8151–8162). We have investigated here a helix-sense induction in an optically inactive N-terminal-free nonapeptide (1) through the screening of several peptide species that differ in chiral sequence, chain length, and C-terminal group. Helix-sense induction in peptide 1 depends largely on both the C-terminal chirality and carboxyl group in the external peptide, in which N-carbonyl-blocked amino acids, “monopeptide acids,” should be the minimum requirement for effective induction. N-Protected mono- to tetrapeptides of L-Leu residue commonly induce a right-handed helix. NMR study and theoretical computation reveal that the N-terminal segment of peptide 1 binds the N-protected dipeptide molecule through multipoint coordination to induce a right-handed helix preferentially. The present findings not only will improve our understanding of the chiral roles in peptide or protein helical termini, but also might demonstrate potential applications to chirality-responsive materials based on peptide helical fragments. © 2006 Wiley Periodicals, Inc. Biopolymers 82: 471–481, 2006 This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at
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