Mechanisms of the Interactions Between Antimicrobial Peptides and Model Membranes: A Thermodynamic Hypothesis

Abstract

The relation between the sequences of antimicrobial peptides, their mechanism, and specificity remains poorly understood. The specificity of these polypeptides varies, but there are no striking differences in their sequences. The generally accepted view that binding affinity of cationic peptides toward anionic bacterial membranes determines functional specificity is supported by experiments in model membranes, but beyond that little is clear. On the basis of the mechanisms of several different antimicrobial, cytolytic, and cell-penetrating peptides, including melittin, magainin, cecropin, delta-lysin, mastoparans, transportans, and some of their variants, we have proposed the hypothesis that it is the thermodynamics of peptide insertion into the membrane, from a surface-bound state, that determines their mechanism. We have begun to test this hypothesis by designing variants of the original set of peptides examined. The first results, which include the thermodynamics and kinetics of interaction of these peptides with phospholipid vesicles, are discussed here and compared to those obtained for the original set. This work was supported by NIH grant GM072507.