| Understanding the mechanisms that govern peptide-peptide and peptide-surface interactions is crucial for the design of new peptide-based therapeutic agents. Complementary to experimental techniques, molecular dynamics (MD) simulations offer atomistic insights to these mechanisms that can not be revealed with current experimental methods. Antimicrobial peptides from class IIa and IIb bacteriocins were chosen as model peptides to study key interactions with different substrates. The aims of this work are to: (i) study peptide-peptide and peptide-surface interactions using a two-peptide class IIb bacteriocin, plantaricin S (Pls), (ii) study peptide interactions with different substrates, namely protein, lipid bilayer, and self-assembled monolayers (SAMs), using a class IIa bacteriocin, carnobacteriocin B2 (CbnB2). Pls and five designed peptide fragments were synthesized and evaluated for antimicrobial spectrum. Structure-activity relationship of Pls and derived fragments was studied using activity assays, CD spectroscopy and MD simulations. Specific mechanisms of interaction of CbnB2 with its immunity protein, a model lipid bilayer mimicking cell membrane of Gram positive bacterial cell, and SAMs mimicking heterogeneous (organic) solid surfaces were investigated using MD simulations. Studies conducted with Pls revealed for the first time the antilisterial and antistaphylococcal activity of a class IIb peptide. Structural analyses of the native Pls and active fragments highlight the importance of the helical domains as well as specific key motifs to mediate helix-helix interaction that is necessary for displaying the antimicrobial activity. The simulations conducted in this thesis provide molecular underpinnings of the biophysical forces that govern peptide adhesion to different moieties and substrates. In addition, the effect of surface chemical heterogeneity on peptide dynamics and secondary structure has been highlighted. The studies presented in this thesis enrich the current knowledge about peptide interactions that may potentially help in the rational design of new antimicrobial peptides (AMPs). |
