Designing enzyme-like catalysts: a rhodium(II) metallopeptide case study.

Chemists have long been fascinated by metalloenzymes and their chemistry. Because enzymes are essential for biological processes and to life itself, they present a key to understanding the world around us. At the same time, if chemists could harness the reactivity and selectivity of enzymes in designed transition-metal catalysts, we would have access to a powerful practical advance in chemistry. But the design of enzyme-like catalysts from scratch presents enormous challenges. Simplified, designed systems often don't provide the opportunity to mimic the complex features of enzymes such as selectivity in polyfunctional environments and access to reactive intermediates incompatible with bulk aqueous solution. Extensive efforts by numerous groups have led to remarkable designed metalloproteins that contain complex folds, including well-defined secondary and tertiary structure surrounding complex polymetallic centers. These structural achievements, however, have not yet led to general approaches to useful catalysts; continued efforts and new insights are needed. Our efforts have combined the attributes of enzymatic and traditional catalysis, bringing the benefits of polypeptide ligands to bear on completely nonbiological transition-metal centers. With a focus on designing useful catalytic activity, we have examined rhodium(II) carboxylates, bound to peptide chains through carboxylate side chains. Among other advantages, these complexes are stable and catalytically active in water. Our efforts have centered on two main interests: (1) understanding how Nature's ligand of choice, polypeptides, can be used to control the chemistry of nonbiological metal centers, and (2) mimicking metalloenzyme characteristics in designed, nonbiological catalysts. This Account conveys our motivation and goals for these studies, outlines progress to date, and discusses the future of enzyme-like catalyst design. In particular, these studies have resulted in on-bead, high-throughput screens for asymmetric metallopeptide catalysts. In addition, peptide-based molecular recognition strategies have facilitated the site-specific modification of protein substrates. Molecular recognition enables site-specific, proximity-driven modification of a broad range of amino acids, and the concepts outlined here are compatible with natural protein substrates and with complex, cell-like environments. We have also explored rhodium metallopeptides as hybrid organic-inorganic inhibitor molecules that block protein-protein interactions.