Exploiting diverse stereochemistry of b-amino acids: Toward a rational design of sheet-forming b-peptide systems

Gabor Pohl, Tamas Beke-Somfai, Imre G. Csizmadia, András Perczel

Research output: Contribution to journalArticle

4 Citations (Scopus)


Due to the two methylene groups in their backbone, b-amino acids can adopt numerous secondary structures, including helices, sheets and nanotubes. Chirality introduced by the additional side chains can significantly influence the folding preference of b-peptides composed of chiral b-amino acids. However, only conceptual suggestions are present in the literature about the effect of chirality on folding preferences. Summarizing both the experimental and computational results, Seebach (Chem Biodivers 1:1111-1240, 2004) has proposed the first selection rule on the effect of side chain chirality, on the folding preference of b-peptides. In order to extend and fine-tune the aforementioned predictions of Seebach, we have investigated its validity to the novel type of apolar sheet proposed recently (Pohl et al. in J Phys Chem B 114:9338-9348, 2010). In order to facilitate the rational design of sheet-like structures, a systematic study on the effect of chirality on apolar sheet stability is presented on disubstituted [HCO-b-Ala-b2,3-hAla-b-Ala-NH2]2 model peptides calculated at the M05-2X/6-311-G(d,p)//M05-2X/6-31G(d) and B3LYP/6-311-G(d,p)// B3LYP/6-31G(d) levels of theory both in vacuum and in polar and apolar solvents. In addition, both types of apolar sheets were investigated; the one with two strands of identical (AA) and enantiomeric (AB) backbone structure. Our results show that heterochirally disubstituted sheets have the greatest preference for sheet formation (DG * -11 kcal mol-1). However, in contrast to Seebach's predictions, homochiral disubstitution itself does not necessarily disrupt the sheet structure, rather it could result stable fold (DG * -5 kcal mol-1). Results indicate that both the methyl group orientation and the local conformational effect of substitution affects sheet stability, as point chirality was found to have influence only on the backbone torsional angles. These results enabled us to extend and generalize Seebach's predictions and to propose a more general and accurate rule of thumb describing the effect of chirality on sheet stability. This offers an easy-to-use summary on how to design b-peptide sheet structures. We conclude that heterochirally disubstituted models are the best candidates for sheet formation, if the two strands are substituted in a way to create identical torsional angle sets on the two backbones for ideal hydrogen-bonding pattern. With adequately selected side chains, homochirally disubtituted derivatives may also form sheet structures, and the position of methyl groups would prevent assembly of more than two strands making it ideal to create hairpins.

Original languageEnglish
Pages (from-to)735-749
Number of pages15
JournalAmino Acids
Issue number2
Publication statusPublished - Aug 1 2012


  • B-amino acid
  • B-peptide
  • Chirality
  • Computational chemistry
  • Foldamer
  • Sheet structures

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Organic Chemistry

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