Exploiting diverse stereochemistry of β-amino acids: toward a rational design of sheet-forming β-peptide systems.
ABSTRACT Due to the two methylene groups in their backbone, β-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 β-peptides composed of chiral β-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 β-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-β-Ala-β(2,3)-hAla-β-Ala-NH(2)](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 (ΔG ~ -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 (ΔG ~ -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 β-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.
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ABSTRACT: To develop a theoretical method for prediction of transcellular permeability to peptides. The dynamic molecular surface properties of 19 oligopeptide derivatives, divided into three homologous series were calculated. The dynamic molecular surface properties were compared with commonly used experimental predictors of membrane permeability such as partition coefficients. Relationships between the dynamic molecular surface properties and intestinal epithelial permeability, as determined in Caco-2 cell monolayers, were used to develop a model for prediction of the transmembrane permeability to the oligopeptide derivatives. A theoretical model was derived which takes both the polar and non-polar part of the dynamic molecular surface area of the investigated molecule into consideration. The model provided a strong relationship with transepithelial permeability for the oligopeptide derivatives. The predictability of transepithelial permeability from this model was comparable to that from the best experimental descriptor. To our knowledge, this is the first example of a theoretical model that gives a satisfactory relationship between calculated molecular properties and epithelial permeability to peptides by accounting for both the hydrogen bonding capacity and the hydrophobicity of the investigated molecule. This model may be used to differentiate poorly absorbed oligopeptide drugs at an early stage of the drug discovery process.Pharmaceutical Research 03/1999; 16(2):205-12. · 4.74 Impact Factor
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ABSTRACT: A beta-hairpin conformation and extended beta-pleated sheet assembly have been characterized by single crystal x-ray diffraction for the synthetic peptide t-butoxycarbonyl--beta-Phe-beta-Phe-D-Pro-Gly-beta-Phe-beta-Phe-methyl ester [beta-Phe: (S)-beta(3) homophenylalanine]. The centrally located D-Pro-Gly segment nucleates a chain reversal in a type II' beta-turn conformation. Two intramolecular cross-strand hydrogen bonds stabilize the peptide fold. Intermolecular NH...O[double bond]C hydrogen bonds (two on each side of the hairpin) connect the hairpins into an infinitely extended beta-sheet. The beta-residues cause all C[double bond]O groups to point in the same direction, resulting in a "polar" sheet by the unidirectional alignment of NH...O[double bond]C hydrogen bonds. In contrast, beta-sheets formed by alpha-residues have alternating directions for the hydrogen bonds, thus resulting in an "apolar" sheet. The crystallographic parameters for C(53)H(66)N(6)O(9) x CH(3)OH are: space group P2(1), a = 9.854(2) A, b = 10.643(2) A, c = 25.296(4) A, beta = 100.39(2) degrees, Z = 2, agreement factor R(1) = 0.065 for 3,706 data observed >4 sigma(F) and a resolution of 0.90 A.Proceedings of the National Academy of Sciences 04/2002; 99(8):5160-4. · 9.74 Impact Factor
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ABSTRACT: Parallel or polar strands of beta-peptides spontaneously form nanotubes of different sizes in a vacuum as determined by ab initio calculations. Stability and conformational features of [CH3CO-(beta-Ala)k-NHCH3]l (1 < or = k < or = 4, 2 < or = l < or = 4) models were computed at different levels of theory (e.g., B3LYP/6-311++G(d,p)// B3LYP/6-31G(d), with consideration of BSSE). For the first time, calculations demonstrate that sheets of beta-peptides display nanotubular characteristics rather than two-dimensional extended beta-layers, as is the case of alpha-peptides. Of the configurations studied, k = l = 4 gave the most stable nanotubular structure, but larger assemblies are expected to produce even more stable nanotubes. As with other nanosystems such as cyclodextrane, these nanotubes can also incorporate small molecules, creating a diverse range of applications for these flexible, biocompatible, and highly stable molecules. The various side chains of beta-peptides can make these nanosystems rather versatile. Energetic and structural features of these tubular model systems are detailed in this paper. It is hoped that the results presented in this paper will stimulate experimental research in the field of nanostructure technology involving beta-peptides.Journal of the American Chemical Society 04/2006; 128(15):5158-67. · 10.68 Impact Factor