Theoretical Analysis of Secondary Structures of β-Peptides

Abstract

Unlike alpha-amino acids, peptides formed from beta-amino acids (beta-peptides) display stability toward enzymatic degradation and may form turns and helices with as few as four residues. Because both the C alpha and C beta of the beta-amino acid may bear substituents, a large number of beta-amino acids can be synthesized. Beta-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, beta-amino acids have been increasingly used as building blocks for molecular design and pharmaceutical applications. To explain the conformational features of beta-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 beta-peptides. We start by studying the basic local conformational features of beta-peptides using di- and tripeptide models. Then, various secondary structures of unsubstituted beta-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 beta-peptide backbone. The 14-helix, 12-helix, and 10-helix structures have similar stabilities for beta-peptide backbones of four to six residues. The substituent effects on the stabilities of beta-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-beta(2)/beta(3)-peptides, unlike-beta(3)/beta(3)-peptides, and beta(3)/beta-hGly-peptides because these substitution patterns do not cause steric problems for the 10/12-helix. Beta(3)-peptides, beta(2)-peptides, and beta (2,3)-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 beta-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.

Synthesis of Chemically Modified Bioactive Peptides: Recent Advances, Challenges and Developments for Medicinal Chemistry

“…Despite not being entirely artificial, b-amino acids cannot usually be degraded quickly in vivo. Peptides containing only b-amino acids form different helical or b-strand structure motifs, in a similar way to peptides consisting of purely a-amino acids [105]. Incorporation of one b-amino acid into a cyclic peptide consisting otherwise of a-amino acids elongates the backbone by one carbon atom for each incorporated b-amino acid, thus allowing for an adjustment of the ring size and, most importantly, the overall conformation in cyclic peptides.…”

Mechanical unfolding pathway of a model β-peptide foldamer

“…In addition to their interesting properties from a chemical point of view, small β-peptides allow detailed simulation studies of their structure and of the unfolding kinetics. 33,36,37 In the present paper, we report the results of MD simulations of the mechanical unfolding of a well studied heptamer of β 3 -amino acids in methanol solvent. [38][39][40][41][42]35 The structure and the sequence are given in Fig.…”

Intermolecular interactions in uracil–nitrous acid complexes: structures, binding energy, topological properties, and nuclear magnetic resonance study

“…Figure 5. Relationship between charge transfer energy E (2) and corresponding hydrogen bonding distances at B3LYP/aug-cc-pVDZ level. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]…”

“…[1][2][3][4][5] Hydrogen bonds play important roles in biological systems. [6] They are relatively easily broken and reformed, and therefore, they provide the delicate balance required by life molecules, such as proteins and DNA.…”