This dissertation focuses on the theoretical studies of peptide formed by unnatural amino acids - β-peptides, γ-peptides and oxa-peptides, composed of β-amino acids, γ-amino acids and aminoxy acids - using ab initio quantum mechanics and molecular mechanical computational methods....[ Read more ]

This dissertation focuses on the theoretical studies of peptide formed by unnatural amino acids - β-peptides, γ-peptides and oxa-peptides, composed of β-amino acids, γ-amino acids and aminoxy acids - using ab initio quantum mechanics and molecular mechanical computational methods.

Systematic studies of β-peptides are presented in Chapters 2- 4. In Chapter 2, the conformations of unsubstituted, α-substituted and β-substituted β-dipeptide models are studied, focusing on low-energy and secondary structure-related conformers. The substituent effect on the secondary structures - β-sheet, 14-helix and 12-helix - are investigated. The calculation results indicate that the C6 conformers are most stable for all dipeptide models. Conformers corresponding to the 12- and 14- helices also have low energies in polar solvents. β³-Peptides form the 14-helix very easily. In Chapter 3, the substituent effects on the formation of the 14-helix and 10/12-helix are discussed in great detail based on the calculation results of tri- and hepta-peptide models. The β-peptides have an intrinsic preference for the formation of 10/12-helix. Thus, mixed β²,β³-peptides favor the 10/12-helix, in agreement with experimental observation. The 14-helix is favorable for β³-peptides because the 10/12-helix is destabilized by half of Cγsubstituents. A qualitative model has been developed to evaluate the stability of the 10/12-mixed helix, which is of predicting power. In Chapter 4, the conformational features of α,β-disubstituted and α-hydroxyl β-peptides are explored. Our calculation results indicate that the C6 conformer is most stable for (2S,3S)-α,β-disubstituted dipeptide models and the 14-helix is also favorable for peptides consisting of (2S,3S)-α,β-disubstituted β-amino acid. However, the (2S,3R)-α,β-disubstituted ppeptides are easy to form β-sheet secondary structure.

Chapter 5 presents a systematic study on peptides formed aminoxy acids or oxa-peptides, analogs of β-peptides, are studied using mono-, di-, tri- and penta-peptide models in Chapter 5. The calculation results show that there is a strong tendency to form a stable eight-membered-ring hydrogen bond between adjacent aminoxy acid residues. These eight-membered-ring hydrogen-bonded structures are predicted to be also stable in pentamer, suggesting an 1.8₈ helix. The substituent effects at α-carbon on the formation of helical and cyclic structure are also studied. We predict that the homo-chiral oxa-peptides prefer to form a helix, while the alternating R- and S- oxa-peptides prefer to form a cyclic structure.

A preliminary study on the conformational feature of γ-peptides is presented in Chapter 6. For an unsubstituted hexapeptide model, a C9-helix and a 14-helix are of similar stabilities, while a 12-helix is less stable by about 3 kca.l/mol in methanol solution. Conformational analysis and calculations suggest that γ-substituents stabilize the 14-helix and destabilize the 12-helix. On the other hand, γ-substituents destabilizes the g-helix and the 14-helix but promotes the formation of the 12-helix. It is also predicted that the 12-helix is most favorable for unprotected α-substituted α-peptides.