Arginine/Tryptophan‐Rich Cyclic α/β‐Antimicrobial Peptides: The Roles of Hydrogen Bonding and Hydrophobic/Hydrophilic Solvent‐Accessible Surface Areas upon Activity and Membrane Selectivity

The bacterial selectivity of an amphiphilic library of small cyclic α/β‐tetra‐, α/β‐penta‐, and α/β‐hexapeptides rich in arginine/tryptophan (Arg/Trp) residues, which contains asymmetric backbone configurations and differ in hydrophobicity and alternating d,l ‐amino acids, was investigated against Bacillus subtilis and Escherichia coli . The structural analyses showed that the peptides tend to form assemblies of different shapes. All‐ l ‐peptides, especially the most hydrophobic pentamers, were more strongly anti‐ B .  subtilis . With the exception to cyclo(Phe‐ d ‐Trp‐β 3 hArg‐Arg‐ d ‐Trp) (Phe=phenylalanine), the peptides had no effects on inner membrane of E .  coli , but lyzed the lipopolysaccharide layer according to their activity pattern. The activities adversely changed with a decrease in the number of amide intramolecular hydrogen bonds in assemblies of diastereomeric peptides and the ratio of hydrophobic/hydrophilic solvent‐accessible surface areas. The remarkable enhanced entropic contribution for the partitioning of the least conformationally constrained cyclo(Trp‐ d ‐Phe‐β 3 hTrp‐Arg‐ d ‐Arg) sequence into the membranes supported the strong self‐assembly behavior, therefore making the peptide less penetrable through the E .  coli outer layer.