Structure-guided de novo design of α-helical antimicrobial peptide with enhanced specificity

Abstract

In the present study, the 26-residue peptide sequence Ac-KWKSFLKTFKSAKKTVLHTALKAISS-amide (peptide P) was utilized as the framework to study the effects of introducing hydrophilic amino acid lysine on the nonpolar face of the helix on peptide biological activities. Lysine residue was systematically used to substitute original hydrophobic amino acid at the selected locations on the nonpolar face of peptide P. In order to compensate for the loss of hydrophobicity caused by lysine substitution, leucine was also used to replace original alanine to increase peptide overall hydrophobicity. Hemolytic activity is correlated with peptide hydrophobicity. By introducing lysine on the nonpolar face, we significantly weaken peptide hemolytic activity as well as antimicrobial activity. However, by utilizing leucine to compensate the hydrophobicity, we improve antimicrobial activity against both Gram-negative and -positive bacteria. Peptide self-association ability and hydrophobicity were also determined. This specific rational approach of peptide design could be a powerful method to optimize antimicrobial peptides with clinical potential as peptide antibiotics.