Modeling the secondary structures of the peptaibols antiamoebin I and zervamicin II modified with<Emphasis Type="SmallCaps"> D</Emphasis>-amino acids and proline analogues

Antiamoebin I (AAM-I) and zervamicin II (Zrv-IIB) are peptaibols that exert antibiotic activity through the insertion/disruption of cell membranes. In this study, we investigated how the folding of these peptaibols are affected when some of their native residues are replaced with proline analogues and asymmetrical D-α,α-dialkyl glycines (two classes of noncanonical amino acids). Systematic substitutions of native Aib, Pro, Hyp, and Iva residues were performed to elucidate the folding properties of the modified peptaibols incorporating noncanonical residues. The secondary structure of a peptaibol influences its ability to incorporate into membranes and therefore its function. Our findings reveal that native Zrv-IIB unfolds considerably in water. The presence of Iva and the noncanonical proline analogue cis-3-amino-L-proline (ALP) in both peptaibols induces helical structures. Inserting asymmetric glycines such as α-methyl-D-leucine (MDL) and α-methyl-D-phenylalanine (MDP) into the peptaibols induces folding. This preorganization in water may help to overcome the energy barrier required for peptaibol insertion into the membrane, as well as to facilitate the formation of transmembrane channels.

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Graphical abstract AAM-I and Zrv-IIB peptidomimetics carrying MDL and ALP noncanonical amino acids, exhibiting improved helical secondary structure in water