Computationally designed β‐turn foldamers of γ‐peptides based on 2‐(aminomethyl)cyclohexanecarboxylic acid

Lee

2015

New J. Chem.

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The conformational preferences of helix foldamers have been studied in oligo-g-peptides composed of 2-aminocyclopentylacetic acid (gAc 5 a) with a cyclopentyl constraint on the C b -C g bond using density functional methods. Although the gAc 5 a (1) dipeptide with homochiral (1S,2S) configurations exhibits a strong preference for the right-handed (P) 9-membered helix foldamer in chloroform and water, oligopeptides composed of gAc 5 a (1) preferentially adopt (P)-2.5 14 -helices due to the favored conformational energy produced as the peptide sequence becomes longer and as solvent polarity increases. The calculated mean backbone torsion angles and helical parameters for 14-helical foldamers composed of gAc 5 a (1) are consistent with those measured in the X-ray structures of penta-and hexapeptides composed of C a -ethyl-gAc 6 a and 14-helical foldamers composed of gAc 6 a (1) with cyclohexyl constraints.However, the substitution of cyclopentane constraints in the backbone differentially changed the conformational preference and/or handedness for helix foldamers when compared with other oligo-g-peptides with different cycloalkane positions or size constraints. The conformational preferences of the oligo-gAc 5 a peptides obtained here are expected to provide useful information for the structure-based design of biologically active g-peptides with specific functions.

Section: Introductionmentioning

confidence: 96%

Helix foldamers of γ-peptides based on 2-aminocyclopentylacetic acid

Lee

2015

New J. Chem.

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“…1 hydrogen bond, and these turns facilitate the formation of b-hairpin structures. Based on density functional theory (DFT) calculations, Kang and Byun suggested that the di-c-peptide segment could be used as a b-turn motif in b-hairpins of Ala-based a-peptides and gramicidin S. 38 Recently, Mathieu et al reported that 4-amino-(methyl)-1,3-thiazole-5-carboxylic acid residues promoted a twist turn in hybrid acaa-tetrapeptides and in a bioactive analog of gramicidin S. 39 Although many computational studies have evaluated the propensities of dipeptides to form various types of bturns, 7,[40][41][42][43][44][45][46] no computational studies have examined the formation of b-turn and b-hairpin structures in peptides containing the Asn-Gly segment. Here, we used DFT methods to study the propensities of oligopeptides containing these segments to adopt b-turn and b-hairpin conformations in CH 2 Cl 2 and water.…”

mentioning

confidence: 99%

Propensities of peptides containing the Asn‐Gly segment to form β‐turn and β‐hairpin structures

Yoo

2016

Biopolymers

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The propensities of peptides that contain the Asn-Gly segment to form β-turn and β-hairpin structures were explored using the density functional methods and the implicit solvation model in CH2 Cl2 and water. The populations of preferred β-turn structures varied depending on the sequence and solvent polarity. In solution, β-hairpin structures with βI' turn motifs were most preferred for the heptapeptides containing the Asn-Gly segment regardless of the sequence of the strands. These preferences in solution are consistent with the corresponding X-ray structures. The sequence, H-bond strengths, solvent polarity, and conformational flexibility appeared to interact to determine the preferred β-hairpin structure of each heptapeptide, although the β-turn segments played a role in promoting the formation of β-hairpin structures and the β-hairpin propensity varied. In the heptapeptides containing the Asn-Gly segment, the β-hairpin formation was enthalpically favored and entropically disfavored at 25°C in water. The calculated results for β-turns and β-hairpins containing the Asn-Gly segment imply that these structural preferences may be useful for the design of bioactive macrocyclic peptides containing β-hairpin mimics and the design of binding epitopes for protein-protein and protein-nucleic acid recognitions. © 2016 Wiley Periodicals, Inc. Biopolymers 105: 653-664, 2016.

“…GS adopted a C 2 ‐symmetric antiparallel β‐sheet with two type II′ β‐turns at the d ‐Phe‐Pro sequences . Several GS analogs, which contained thioindolizines, indolizines, sugar amino acids and their homologs, d ‐Pro‐Phe, morpholine amino acids, or di‐γ‐peptide at the d ‐Phe‐Pro sequence, have been studied with the aim of designing potent antimicrobial agents …”

Section: Resultsmentioning

confidence: 99%

“…The trigonal crystal of GS contained one and a half crystallographically independent peptide molecules (A and B) (i.e., GS A and GS B ), the latter of which contained the molecular C 2 symmetry axis . GS B was found to be more stable by 1.98 kcal mol −1 in electronic energy than GS A at the SMD M06‐2X/6–31G(d) level of theory in water . For comparison, we also optimized the structure of GS B at the same level of theory in CH 2 Cl 2 .…”

Section: Resultsmentioning

confidence: 99%

Hairpin formation promoted by the heterochiral dinipecotic acid segment: A DFT study

Park

2015

Biopolymers

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Conformational preferences for the turn and β-hairpin structures of Ala-based peptides [Ac-Ala(n)-(R)-Nip-(S)-Nip-Ala(n)-X (n = 0-2; X = NHMe or NMe2)] containing nipecotic acid (Nip) residues were carried out using the density functional M06-2X and the implicit solvation model SMD in CH2Cl2 and/or water. The turn structure of the (R)-Nip-(S)-Nip segment with a C10 H-bond between two terminal groups was found to be most preferred (populated at 98.9%) in CH2Cl2; this structure is consistent with IR and (1)H NMR results. The stabilities of the β-hairpins containing the (R)-Nip-(S)-Nip segment as a turn motif relative to the extended structures increased with peptide sequence length. The relative strengths of the H-bonds between the carbonyl oxygen and the amide hydrogen appeared to be responsible for stabilizing the turn and β-hairpin structures in CH2Cl2. In addition, the (R)-Nip-(S)-Nip segment exhibited the capability to be incorporated into one of the two β-turn motifs of gramicidin S (GS). The structure of this GS derivative (GS-Nip2 ) was generally similar to the native peptide but was less hydrophobic and it is therefore expected to exhibit lower hemolytic activity; however, further experiments are needed to evaluate its antimicrobial activity. The structure of GS-Nip2 was somewhat more flexible than GS in solvents of higher polarity. Thus, our calculated results regarding the turn and β-hairpin motifs of the (R)-Nip-(S)-Nip segment indicate that this structure might be useful for the design of bioactive macrocyclic peptides containing β-hairpin mimics as well as binding epitopes in protein-protein and protein-nucleic acid recognitions.