Lewis, J.C.

ACS Catal. 2013, 3, 2954-2975, 10.1021/cs400806a

Transition metal catalysts and enzymes possess unique and often complementary properties that have made them important tools for chemical synthesis. The potential practical benefits of catalysts that combine these properties and a desire to understand how the structure and reactivity of metal and peptide components affect each other have driven researchers to create hybrid metal–peptide catalysts since the 1970s. The hybrid catalysts developed to date possess unique compositions of matter at the inorganic/biological interface that often pose significant challenges from design, synthesis, and characterization perspectives. Despite these obstacles, researchers have developed systems in which secondary coordination sphere effects impart selectivity to metal catalysts, accelerate chemical reactions, and are systematically optimized via directed evolution. This perspective outlines fundamental principles, key developments, and future prospects for the design, preparation, and application of peptide- and protein-based hybrid catalysts for organic transformations.

Marshall, N.M.

Comprehensive Inorganic Chemistry II 2013, 565-593, 10.1016/B978-0-08-097774-4.00325-9

Metalloproteins catalyze numerous biological reactions ranging from photosynthesis, respiration, nitrogen fixation to signal transduction and complex chemical reactions. It is thus not surprising that metalloproteins account for almost one-half of the total number of proteins in nature. A considerable effort has been directed toward understanding the structure–function relationships using native proteins. However, it is an ultimate challenge to design metalloproteins using only the minimal features required to reproduce their functionalities as well as confer them with novel and unprecedented functionalities learned from the design process. In this chapter, we review some recent successes in the field of metalloprotein design using either de novo designed or native protein scaffolds. Furthermore, metalloprotein design employing unnatural amino acids or non-native cofactor are summarized. Finally, methodologies employing rational design, combinatorial selection, or both methods are also discussed.

Seelig, B.; Szostak, J.W.

Nature 2007, 448, 828-831, 10.1038/nature06032

Enzymes are exceptional catalysts that facilitate a wide variety of reactions under mild conditions, achieving high rate-enhancements with excellent chemo-, regio- and stereoselectivities. There is considerable interest in developing new enzymes for the synthesis of chemicals and pharmaceuticals1,2,3 and as tools for molecular biology. Methods have been developed for modifying and improving existing enzymes through screening, selection and directed evolution4,5. However, the design and evolution of truly novel enzymes has relied on extensive knowledge of the mechanism of the reaction6,7,8,9,10. Here we show that genuinely new enzymatic activities can be created de novo without the need for prior mechanistic information by selection from a naive protein library of very high diversity, with product formation as the sole selection criterion. We used messenger RNA display, in which proteins are covalently linked to their encoding mRNA11, to select for functional proteins from an in vitro translated protein library of >1012independent sequences without the constraints imposed by any in vivo step. This technique has been used to evolve new peptides and proteins that can bind a specific ligand12,13,14,15,16,17,18, from both random-sequence libraries12,14,15,16 and libraries based on a known protein fold17,18. We now describe the isolation of novel RNA ligases from a library that is based on a zinc finger scaffold18,19, followed by in vitro directed evolution to further optimize these enzymes. The resulting ligases exhibit multiple turnover with rate enhancements of more than two-million-fold.