Stabilizing secondary structure in peptides and proteins

The studies represented in this work address questions concerning the stability of secondary structure in peptides and proteins. About half of the amino acid residues in globular proteins adopt a secondary structure conformation. There is an ongoing debate on the determinants of secondary structure. Being able to predict secondary structure is an important question in the protein folding problem. It will allow us to transform the wealth of genetic data directly into protein structure. The reoccurrence of secondary structure also opens an avenue for protein engineering. If transferable motifs could be identified that stabilize secondary structure, they could in principle be introduced to stabilize a variety of proteins. Stabilizing proteins will make them less susceptible towards degradation and would facilitate enzymatic reactions at higher temperatures.;The first three studies address fundamentals of the formation of secondary structure in peptides. Chapter Three explores the phenomenon of the formation of alpha-helix in ultra short peptides. Before this study, it was unknown if peptides with an average length shorter than 12 could adopt an alpha-helical conformation. The study describes the induction of alpha-helicity by glutamic acid side chains in short peptides. Chapters Four and Five address the secondary structure inducing ability of alanine. The unexpected formation of beta-sheet by alanine based peptides is discussed in chapter Four. The role of stretches of alanine in the formation of beta-sheets in spider silk is elucidated. Chapter Five concerns the important question of the intrinsic helix stabilizing ability of alanine. Are small alanine based peptides helical because of the intrinsic helix forming tendency of alanine or because of residues introduced to facilitate solvation?;The last two studies involve the stabilization of proteins through the stabilization of secondary structure elements. Chapter Six explores the introduction of helix 'friendly' residues and single and multiple salt bridges in a model protein GCN4, a leucine zipper. While the last chapter analyses the effect of a capping box into GCN4 on the structure and stability of the protein. Multiple elements introduced in the leucine zipper have been shown to stabilize the protein significantly and may prove to be universal stabilizers.