Computer simulations of antimicrobial peptides

Disease causing microbes are becoming resistant to common antibiotics, and are thus emerging as a serious threat to public health. Researchers are being forced to look for novel antibiotic formulations to combat this menace. Optimism in antimicrobial peptides (AMPS) as substitutes of conventional antibiotics has been triggered by knowledge of their quick and strong antimicrobial action, as well as the non-specific membrane-mediated mechanism of AMP-induced cell death. However, the design of novel AMPS with attenuated host cell toxicity has been impeded by a lack of molecular-scale fundamental knowledge of AMP-membrane interaction events. Experimental systems can be complimented by computer simulations to probe peptide-membrane systems to the spatial and temporal resolution required to develop this insight. In this thesis, we have used all-atom molecular dynamics simulations of AMPS in membrane mimics to decipher which sequence and structure components of AMPS are responsible for activity and toxicity. Lipid bilayers and detergent micelles are both used as models for membrane interfaces. Zwitterionic micelles of dodecylphosphocholine (DPC) and bilayers of the zwitterionic lipid dilauroylphosphatidylcholine (DLPC) were used to model mammalian membrane interfaces, while simulations were also implemented in anionic sodiumdodecylsulfate (SDS) micelles to evaluate the peptide structure in the presence of an anionic bacterial membrane interface mimic. To develop comprehensive hypotheses, simulations were implemented for the three most common structural classes of AMPs: unstructured, alpha-helical and beta-sheet ones.; We found that for different structural types of AMPs different types of biophysical interactions determined the dynamics of peptide-membrane interaction, the membrane-bound structure of the peptide and the equilibrium orientation of the AMP near the interface. For the tryptophan and proline rich AMP indolicidin, intra-peptide and peptide-lipid cation-pi interactions stabilized the structure in the zwitterionic DPC micelle, while the absence of these interactions led to an ill-defined extended structure in the anionic SDS micelle. On the other hand, for helical peptides, the structure was stable in SDS. Only toxic peptides were equally helical in both zwitterionic interfaces and anionic interfaces. This role for interfacial electrostatics was suggested for the first time. The protonated N-terminus of the beta-hairpin peptide protegrin-1 anchored it to the DLPC bilayer. A novel, previously undetected C-terminal bend in the membrane-bound structure was observed. The bend was induced by unconventional intra-peptide sidechain-backbone hydrogen bonding, which compensated for the unfavorable free energy of insertion of polar groups into the hydrophobic membrane core. (Abstract shortened by UMI.)...