Protein Design: Template‐Assembled Synthetic Proteins

Abstract

The introduction of the template-assembled synthetic protein (TASP) concept for the de novo design of proteins has provided a very powerful new tool for the construction of artificial tertiary structures. TASPs are constructed by the covalent attachment of amphiphilic secondary structure blocks to a topological template, resulting in a non-linear chain architecture of the target molecules. A key feature of this approach is that the template serves to reinforce and direct the folding of the secondary structure elements into predetermined tertiary structures. Having used stepwise solid-phase peptide synthesis (SPPS) in combination with linear oligopeptide templates in the initial stages of our research on TASPs we are now pursuing refined structural and synthetic approaches in the construction of the next generation of TASP molecules. These include the synthesis by SPPS of four-helix bundle TASPs using new cyclic templates (containing either S-S bridges or beta-turn mimetics) as well as conventional fragment condensation strategies using protected fragments. The conformational properties of these new TASPs are now under investigation, with special emphasis on the relationship between overall conformation and the nature of the topological template.