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 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 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.