Modeling of peptaibol analogues incorporating nonpolar α,α-dialkyl glycines shows improved α-helical preorganization and spontaneous membrane permeation.

In this study, we investigate the effect of nine noncanonical α,α-dialkyl glycines on the structure, dynamics, and membrane permeation properties of a small peptaibol, peptaibolin. The noncanonical amino acids under study are Aib (α-amino isobutyric acid), Deg (α,α-diethyl glycine), Dpg (α,α-dipropyl glycine), Dibg (α,α-di-isobutyl glycine), Dhg (α,α-dihexyl glycine), DΦg (α,α-diphenyl glycine), Db(z)g (α,α-dibenzyl glycine), Ac6c (α,α-cyclohexyl glycine), and Dmg (α,α-dihydroxymethyl glycine). It is hypothesized that these amino acids are able to induce well-defined secondary structures in peptidomimetics. To investigate this hypothesis, we designed new peptaibolin peptidomimetics by replacing the native Aib positions with a new α,α-dialkyl glycine. We show that Dhg and Ac6c noncanonical amino acids are able to induce α-helix secondary structures of peptaibolin in water, which are not present in the native structure. We also demonstrate that the α,α-dialkyl glycines increase the membrane permeability of peptaibolin in 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) membranes. However, there is no apparent correlation between increased helicity and membrane permeability. In summary, we show that some α,α-dialkyl glycines under study induce the formation of α-helix secondary structures in peptaibolin and promote spontaneous membrane permeation. Our findings increase the knowledge of the membrane permeability and folding of peptides incorporating α,α-dialkyl glycines.