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

The proton nmr and CD spectra of gramicidin S (GS) cyclic-(Val^1,1′-Orn^2,2′-Leu^3,3′-D-Phe^4,4′-Pro^5,5′)₂ and of GS analogs—namely, D-Ala^4,4′]-GS, Gly^4,4′]-GS, and L-Ala^4,4′]-GS—were analyzed. The molecular conformation of D-Ala^4,4′]-GS is similar to that of GS, with the trans form about the D-Ala-Pro peptide bond. The molecular conformation of Gly^4,4′]-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, Gly^4,4′]-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 Gly^4,4′]-GS and L-Ala^4,4′]-GS in DMSO-d₆ and for L-Ala^4,4′]-GS in TFE solution. The large temperature dependences of α-proton chemical shifts of L-Ala^4,4′]-GS in DMSO-d₆ solution indicate that the conformer equilibrium changes with temperature. The GS-type conformation is not formed in L-Ala^4,4′]-GS. The two active peptide analogs, D-Ala^4,4′]-GS and Gly^4,4′]-GS, interact with the phospholipid membrane, taking the GS-type conformation. By contrast, an inactive analog, L-Ala^4,4′]-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.