| This thesis describes a series of structural and spectroscopic studies conducted on a number of antibacterial peptides. In Chapter 2, a sequence length dependence on beta-sheet formation in small cyclic peptides (gramicidin S analogs) is described. 1H-NMR and CD data reveal, that small cyclic peptides will form beta-sheets if, and only if, they contain the following features: 2(2n+1) residues [where (n = 1, 2, 3...)], two equally spaced type II' beta-turns (or type I ' beta-turns) and proper placement of turn and sheet forming residues. In Chapter 3, the synthesis and characterization of D-Leucocin A is described. This represents the first synthesis of an all-D-amino acid class IIa bacteriocin. We show that the unnatural D-enantiomer of Leucocin A is devoid of activity. This result strongly suggests a chiral recognition step is necessary to Leucocin A's mechanism of antibacterial action. Chapter 4 details, by way of 1H-NMR spectroscopy and molecular dynamics, the structural determinants of type II' beta-turn formation. The gramicidin S model is used to determine the effects of: (a) backbone chirality, (b) backbone N-alkylation and (c) side-chain/sidechain interaction, on beta-hairpin and type II' beta-turn formation. It is shown, that proper backbone chirality may account for up to 60%, N-alkylation for up to 20% and proper side-chain/side-chain interactions for up to 10% of type II' beta-turn stabilization. In Chapter 5, the folding and unfolding kinetics of small cyclic beta-hairpins (gramicidin S analogs) is described. These studies were performed by temperature-jump IR, and the results correlated to all-atom molecular dynamics simulations in an attempt to gain detailed structural and dynamic insight into the unfolding events of beta-sheets. |
