Factors governing helical preference of peptides containing multiple α,α-dialkyl amino acids

The presence of multiple α,α-dialkyl amino acids such as α-methylalanine (α-aminoisobutyric acid, Aib) leads to predominantly helical structures, either with α-helical or 3₁₀-helical hydrogen bonding patterns. The crystal structure of emerimicin-(1-9) benzyl ester (Ac-Phe-Aib-Aib-Aib-Val-Gly-Leu-Aib-Aib-OBzl) reported here shows essentially pure α-helical character, whereas other similar compounds show predominantly 3₁₀-helical structures. The factors that govern helical preference include the inherent relative stability of the α-helix compared with the 3₁₀-helix, the extra hydrogen bond seen with 3₁₀-helices, and the enhanced electrostatic dipolar interaction of the 3₁₀-helix when packed in a crystalline lattice. The balance of these forces, when combined with the steric requirements of the amino acid side chains, determines the relative stability of the two helical conformations under a given set of experimental conditions.