Gramicidin S analogs with a D‐Ala, Gly, or L‐Ala residue in place of the D‐Phe residue: Molecular conformations and interactions with phospholipid membrane

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AbstractThe proton nmr and CD spectra of gramicidin S (GS) cyclic‐(Val1,1′‐Orn2,2′‐Leu3,3′‐D‐Phe4,4′‐Pro5,5′)2 and of GS analogs—namely, [D‐Ala4,4′]‐GS, [Gly4,4′]‐GS, and [L‐Ala4,4′]‐GS—were analyzed. The molecular conformation of [D‐Ala4,4′]‐GS is similar to that of GS, with the trans form about the D‐Ala‐Pro peptide bond. The molecular conformation of [Gly4,4′]‐GS depends on the solvent composition of dimethylsulfoxide‐d6/trifluoroethanol (DMSO)‐d6/TFE and DMSO‐d6/H2O as well as the solute concentration. In DMSO‐d6 solution, [Gly4,4′]‐GS forms the GS‐type conformation of the monomer at lower concentration. At higher concentration, the GS‐type conformer is converted to the other one that forms molecular aggregates. The cis form about the X‐Pro peptide bonds is found for [Gly4,4′]‐GS and [L‐Ala4,4′]‐GS in DMSO‐d6 and for [L‐Ala4,4′]‐GS in TFE solution. The large temperature dependences of α‐proton chemical shifts of [L‐Ala4,4′]‐GS in DMSO‐d6 solution indicate that the conformer equilibrium changes with temperature. The GS‐type conformation is not formed in [L‐Ala4,4′]‐GS. The two active peptide analogs, [D‐Ala4,4′]‐GS and [Gly4,4′]‐GS, interact with the phospholipid membrane, taking the GS‐type conformation. By contrast, an inactive analog, [L‐Ala4,4′]‐GS, does not interact with phospholipid membrane. The activities of GS analogs are found to correlate to the formation of the GS‐type conformation upon binding with phospholipid membrane.