Dynamic combinatorial libraries of repeats-protein receptors and catalysts

Abstract

De novo design of functional proteins is emerging as a powerful tool to improve or totally alter their original functionality. Such studies shine light on the basic principles that govern protein folding, protein interactions with proteins or other molecules, and may facilitate the development of devices for biotechnology applications. However, the progress towards these goals is limited due to the fact that most of the currently used synthetic scaffolds do not possess surface area that is large enough to coordinate complex and massive biological ligands. I suggest here the design, synthesis and evaluation of artificial Leucine Rich Repeats (LRR) proteins as universal recognition entities for the preparation of receptors and biomimetic catalysts. The LRR motifs possess extended ligand binding surfaces and play central role in a wide scope of biomolecular recognition events in cells. Their analogs will be prepared by chemical methods that allow introducing sequence diversity from natural as well as non-natural amino acids. Efficient binders of proteins and nucleic acids ligands, and catalysts for reactions that induce conformational changes in proteins, will be identified in dynamic combinatorial libraries of such proteins, a method by which the host is being selected and amplified by its guest at the expense of competing structures. I anticipate that the modular synthesis and screening approaches will allow the development of LRR binders for large variety of biomolecules, which will be utilized for parallel detection in vitro and within cells.