Antimicrobial peptides (AMPs) are relatively-short chain molecules that living organisms use to defend themselves against a wide range of invading microorganisms such as bacteria and viruses. They selectively bind to and kill microbes over host cells by permeabilizing cell membranes or by inhibiting the biological functions of intra-cellular components. Despite its significance in determining their cell selectivity, however, the cell-concentration dependence of AMP's membrane-perturbing activity has not been criticality examined. In this thesis, we present a physical model for cell selectivity of AMPs, especially its cell-concentration dependence. To this end, we use a coarse-grained model that captures essential molecular details such as lipid composition (e.g., fraction of anionic lipids) and peptide amphiphilicity and charge. In particular, we calculate the surface coverage of peptides in the membrane-perturbing mode as a function of peptide and cell densities: those that bind to the interface between lipid headgroups and tails. This allows us to extract the minimum inhibitory concentration (MIC) and the minimum hemolytic concentration (MHC) of the peptides. Our results show that both MIC and MHC increase as the cell density increases so that the peptide selectivity (given by MHC/MIC) decreases with increasing cell density. Our results will help resolve conflicting interpretations of peptide-selectivity experiments.

Antimicrobial peptides (AMPs) are relatively-short chain molecules that living organisms use to defend themselves against a wide range of invading microorganisms such as bacteria and viruses. They selectively bind to and kill microbes over host cells by permeabilizing cell membranes or by inhibiting the biological functions of intra-cellular components. Despite its significance in determining their cell selectivity, however, the cell-concentration dependence of AMP's membrane-perturbing activity has not been criticality examined. In this thesis, we present a physical model for cell selectivity of AMPs, especially its cell-concentration dependence. To this end, we use a coarse-grained model that captures essential molecular details such as lipid composition (e.g., fraction of anionic lipids) and peptide amphiphilicity and charge. In particular, we calculate the surface coverage of peptides in the membrane-perturbing mode as a function of peptide and cell densities: those that bind to the interface between lipid headgroups and tails. This allows us to extract the minimum inhibitory concentration (MIC) and the minimum hemolytic concentration (MHC) of the peptides. Our results show that both MIC and MHC increase as the cell density increases so that the peptide selectivity (given by MHC/MIC) decreases with increasing cell density. Our results will help resolve conflicting interpretations of peptide-selectivity experiments.