Antimicrobial peptides

Abstract

The structure and activity of a helical antimicrobial peptide with a central proline (P14) and its alanine derivative (P14A) were investigated by various spectroscopic methods, restrained molecular dynamics, and biological assay. Both P14 and P14A exhibited cooperative helix formation in TFE solution, but P14 showed much reduced helical stability than P14A. The model structure exhibited a pronounced kink in P14, in contrast to the uniform helix of P14A. The two peptides showed comparable binding to negatively charged lipids, but P14 had considerably reduced affinity to a neutral lipid. With a destabilized helix, P14 exhibited greater antibacterial activity than P14A. It is presumed that the electrostatic interaction between helical peptides and lipid membranes is the dominant factor for antibacterial activity. Moreover, helical stability can modulate the membrane binding driven by electrostatic interaction. The increased antibacterial activity of P14 implies that the helical kink may play an important role in the disruption of bacterial membranes. Temperature coefficients of amide protons have been investigated by 2D NMR spectroscopy for helical peptides with a central proline (P14) and its alanine derivative (P14A) in an aqueous trifluoroethanol (TFE) solution. The profiles of chemical shifts, exchange rates and solvent perturbations of amide protons are compared with that of temperature coefficients. The periodicity of temperature coefficients coincided exactly with that of chemical shifts. Temperature coefficients of each residue for three different TFE concentrations were obtained for comparison. Upon temperature elevation, the hydrophobic interactions which might be responsible for helical curvature would be weakened. If the helical curvature is diminished during the thermal unfolding process, the most affected residues would be those on the concave (hydrophobic) side of the helix. The unusual behavior of temperature coefficients of amide protons in TFE s...