Theoretical Analysis of Secondary Structures of β-Peptides

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Abstract
Unlike α-amino acids, peptides formed from β-amino acids (β-peptides) display stability toward enzymatic degradation and may form turns and helices with as few as four residues. Because both the Cα and Cβ of the β-amino acid may bear substituents, a large number of β-amino acids can be synthesized. β-Peptides form various well-defined secondary structures, including 14-helix, 12-helix, 10/12-helix, 10-helix, 8-helix, turn structures, sheets, and hairpins. For all of these reasons, β-amino acids have been increasingly used as building blocks for molecular design and pharmaceutical applications. To explain the conformational features of β-peptides, several quantum mechanics and molecular dynamics studies that rationalize the observed conformational features have been reported. However, a systematic account that unifies various factors critical to the conformational features is still lacking. In this Account, we present a detailed analysis of the conformational features of various β-peptides. We start by studying the basic local conformational features of β-peptides using di- and tripeptide models. Then, various secondary structures of unsubstituted β-peptides with differing numbers of residues are investigated using a repeating unit approach to derive the intrinsic backbone conformational features. We find that the 10/12-helix is intrinsically most stable for the β-peptide backbone. The 14-helix, 12-helix, and 10-helix structures have similar stabilities for β-peptide backbones of four to six residues. The substituent effects on the stabilities of β-peptide secondary structures are then analyzed. Combined with the substituent effect and the intrinsic backbone preferences, all experimental observations of secondary structure formation can be understood. For example, the 10/12-helix is favored for like-β2/β3-peptides, unlike-β3/β3-peptides, and β3/β-hGly-peptides because these substitution patterns do not cause steric problems for the 10/12-helix. β3-Peptides, β2-peptides, and β2,3-peptides favor the 14-helix because the substituents in these peptides benefit the 14-helix the most but significantly destabilize the 10/12-helix. Because the 10/12-helix is intrinsically favored and has two favorable positions in each residue for substituents, many more hybrid β-peptides are predicted to exist in this secondary structure, which suggests the need for further experiments. These results are valuable for determining the best use of these building blocks in the design of well-structured molecules with desirable chemical functions.

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