NONNATIVE ARCHITECTURES IN PROTEIN DESIGN AND MIMICRY

Protein design aims to mimic some of the structural and functional pro perties of native proteins [1-6]. The complexity of the folding mechan ism, i.e. the pathway by which a linear polypeptide chain finds its un ique 3D-structure, represents one of the most intriguing hurdles in th is rapidly growing field. In order to bypass this well-known protein-f olding problem [7-10], some years ago we proposed the construction of non-native chain architectures with a high propensity for folding [11- 13]. According to this concept, termed TASP (template-assembled synthe tic proteins), topological templates [14, 15] are used as a built-in d evice for directing covalently attached peptide blocks to a predetermi ned packing arrangement, resulting is branched chain architectures. Re cent progress in the synthetic methodology for assembling peptides now allows us to access the full potential of the TASP concept. In this a rticle, we discuss the state of the art of template-based protein de n ovo design, with special emphasis on progress in peptide synthesis and template design and show that some fundamental questions in protein a ssembly, structure and function can be approached by designing protein mimetics of reduced structural and functional complexity.