CONFORMATION-DEPENDENT ANTIBACTERIAL ACTIVITY OF THE NATURALLY-OCCURRING HUMAN PEPTIDE LL-37

The influence of ion composition, pH, and peptide concentration on the conformation and activity of the 37-residue human antibacterial pepti de LL-37 has been studied. At micromolar concentration in water, LL-37 exhibits a circular dichroism spectrum consistent with a disordered s tructure. The addition of 15 mM HCO3-, SO42-, or CF3CO2- causes the pe ptide to adopt a helical structure, with approximately equal efficienc y, while 160 mM Cl- is less efficient, A cooperative transition from d isordered to helical structure is observed as the peptide concentratio n is increased, consistent with formation of an oligomer, The extent o f alpha-helicity correlates with the antibacterial activity of LL-37 a gainst both Gram-positive and Gram-negative bacteria. Two homologous p eptides, FF-33 and SK-29, containing 4 and 8 residue deletions at the N terminus, respectively, require higher concentrations of anions for helix formation and are less active than LL 37 against Escherichia col i D21. Below pH 5, the helical content of LL-37 gradually decreases, a nd at pH 2 it is entirely disordered, In contrast, the helical structu re is retained at pH over 13. The minimal inhibitory concentration of LL-37 against E. coli is 5 mu M, and at 13-25 mu M the peptide is cyto toxic against several eukaryotic cells, In solutions containing the io n compositions of plasma, intracellular fluid, or interstitial fluid, LL-37 is helical, and hence it could pose a danger to human cells upon release. However, in the presence of human serum, the antibacterial a nd the cytotoxic activities of LL-37 are inhibited.