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Nobel Prize in Chemistry 2018

The 2018 Nobel Prize in Chemistry was awarded to Frances H. Arnold “for the directed evolution of enzymes” and the other half jointly to George P. Smith and Gregory P. Winter “for the phage display of peptides and antibodies”. Together their pioneering work harnesses the processes of evolution for the generation of novel biological compounds. These tools have transformed the production of pharmaceuticals such as monoclonal antibodies and renewable fuels.

This Collection presents research, review, news and comment articles from Nature Research to celebrate the award. The collection content is editorially independent and the sole responsibility of Springer Nature.

Core collection – free

Recent advances in areas such as natural product biosynthesis, synthetic biology and the development of biosensors are providing new opportunities to directly harness evolutionary pressure to identify and optimize compounds with desired bioactivities. This article describes innovations in the key components of such strategies, highlights pioneering examples that indicate their potential, and discusses the scientific gaps and challenges that remain to be addressed to realize this potential more broadly in drug discovery.

Innovation | | Nature Reviews Drug Discovery

From the winners

The intermolecular amination of C–H bonds is an enabling transformation for the synthesis of nitrogen-containing molecules; however, developing catalysts for this class of reactions is very challenging. Now, an iron-based enzyme for this reaction has been engineered, demonstrating that a protein can confer a difficult new function upon an otherwise unreactive base metal.

Article | | Nature Chemistry

A collaborative approach between experiment and simulation has revealed a single mutation in the F/G loop of the newly described nitrating cytochrome P450 TxtE that controls loop dynamics and, more surprisingly, the regioselectivity of the reaction. This mutation is present in a subset of homologous nitrating P450s that produce a previously unidentified biosynthetic intermediate, 5-nitro-L-tryptophan.

Article | | Nature Chemistry

Boron is embedded in the synthesis of organic molecules, for example as the metal catalyst in cross-coupling chemistry, and organoboron compounds are important chemotherapeutics. However, boron is rare in nature and no enzymes that catalyse the formation of carbon–boron (C–B) bonds are known. In this work, Frances Arnold and colleagues report the directed evolution of cytochrome c enzymes from Rhodothermus marinus to develop whole-cell biocatalysts for the synthesis of C–B bonds in Escherichia Coli. The evolved enzymes catalyse the insertion of carbene reagents into the boron–hydrogen bonds of boranes to give chiral organoboranes (either enantiomer) with high levels of stereocontrol. The scope of this transformation includes CF3-substituted products, a motif used in pharmaceuticals. These whole-cell reactions could potentially be incorporated into both natural and engineered metabolic pathways.

Letter | | Nature

The inventor of humanized monoclonal antibodies and cofounder of Cambridge Antibody Technology, Greg Winter, muses on the future of antibody therapeutics and UK life science innovation.

Profile | | Nature Biotechnology

Research

The authors describe methods for the directed evolution of artificial endonuclease and ligase enzymes by X-SELEX, from diverse repertoires of synthetic genetic polymers (XNAzymes). The protocol has been applied to four different XNA chemistries and three different reactions, and it is, in principle, applicable to many more.

Protocol | | Nature Protocols

An artificial aldolase has been optimized using an ultrahigh-throughput microfluidic screening assay. The evolved enzyme exhibits excellent stereoselectivity and broad substrate scope. Structural studies suggest that a Lys-Tyr-Asn-Tyr catalytic tetrad, which emerged during directed evolution, is responsible for the >109 rate enhancement achieved by this catalyst.

Article | | Nature Chemistry

Enzymes selectively stabilize the rate-limiting transition state of the catalysed reaction relative to the ground state. Previous attempts to exploit this idea, for example by using transition-state analogues to elicit antibodies with catalytic activities, have generally failed to deliver true enzyme-like catalysts. In this study, the authors engineered and evolved a computationally designed protein catalyst for the Kemp elimination, a well-studied model system for proton transfer from carbon, into an artificial enzyme that accelerates the chemical reaction 6 × 108 fold, approaching the exceptional efficiency of highly optimized natural enzymes. A high-resolution X-ray crystal structure of the evolved enzyme indicates that well-known catalytic strategies, such as shape complementarity and precisely placed catalytic groups, were successfully harnessed to afford such high rate accelerations.

Letter | | Nature

Artificial metalloenzymes—made by incorporating an abiotic cofactor within a protein scaffold—have the potential to engineer non-natural in vivo reactions. To be of practical use, such catalysts must maintain their activity in a cellular environment, which means overcoming the tendency of introduced metal cofactors to be inhibited by cellular components. This paper demonstrates that directed evolution can overcome this difficulty. Markus Jeschek et al. report on the in vivo evolution of a ruthenium–protein complex that can catalyse olefin metathesis—an archetypal organometallic reaction with no equivalent in nature—in the periplasm of Escherichia coli. The evolved metathase compares favorably with commercial catalysts, shows activity for different metathesis substrates and can be further evolved in different directions by adjusting the protocol.

Letter | | Nature

Enzymatic catalysis offers high selectivity and efficiency for specific chemical reactions in complex environments, but these reactions are limited to those found in nature. Todd Hyster and colleagues report a new method for altering the catalytic behaviour of an enzyme, using the photoexcited state of its cofactor. Nicotinamide-dependent ketoreductases are transformed from a hydride source into a radical initiator and chiral hydrogen atom source. Using the new reactivity of the ketoreductase, the authors carry out enantioselective dehalogenation of lactones by irradiation with visible light, a challenging transformation by traditional small-molecule catalysis.

Letter | | Nature

Allosteric effectors have the ability to modulate protein-ligand interactions in a controlled fashion. Now a novel class of antibody-like affinity reagents, synthetic antigen binders or sABs, are generated in vitro that target either the open or closed form of maltose-binding protein. These sABs can be engineered to control ligand-binding affinities by modulating the transition between different conformations.

Article | | Nature Structural & Molecular Biology

Metals serve as unique structural and functional elements in biology, providing a wealth of reactivities not available in a wholly proteinogenic active site. The computational redesign and directed evolution of zinc enzymes to create a phosphotriesterase provides insights into how these elements can be utilized in the development of new functions.

Article | | Nature Chemical Biology

Reviews, News and Comments

Directed evolution uses laboratory-based evolution to enhance the properties of biomolecules, primarily to generate proteins with optimized or novel activities. This Review discusses the diverse range of technologies for the directed evolution of proteins, particularly methods for generating diversity in the gene library and approaches for screening and selecting for variants with desired properties. The relative strengths and limitations of these approaches are highlighted to guide readers to appropriate strategies.

Review Article | | Nature Reviews Genetics

How can we improve the design of monoclonal antibodies (mAbs) to treat cancer? In this Review, George J. Weiner discusses the characteristics of mAbs that can affect their efficacy, the current approaches that use mAbs in cancer treatment and the numerous ways to enhance the potential of these mAb-based techniques.

Review Article | | Nature Reviews Cancer

Therapeutic antibodies have already improved the lives of many people living with autoimmune diseases such as rheumatoid arthritis and Crohn's disease. But there is still room for improvement. Here, the authors review how the current therapeutic antibodies work and how they might be enhanced to increase efficacy and extend their use.

Review Article | | Nature Reviews Immunology

More than 30 monoclonal antibody-based therapies have been approved for clinical use in the past 25 years. By looking at the strategies that have been used by pharmaceutical companies to develop these products, this Timeline article provides insight into the challenges that will be faced in developing the next generation of therapeutic antibodies.

Timeline | | Nature Reviews Immunology

In 2001, a Review Article in Nature ( http://go.nature.com/t38uzr ) took stock of then-recent advances in biocatalysis — the use of enzymes or microbes to perform synthetic chemistry — and predicted steady development of the technology. In the intervening decade, biocatalysis has become a practical and environmentally friendly alternative to the use of transition-metal-based catalysts in chemical reactions. In a new Review, Bornscheuer et al. revisit the field. We are, they say, witnessing the third wave of biocatalysis, in which enzymes can be engineered with dramatic new activities. The authors highlight the success of biocatalysts in a number of applications, including the synthesis of important commodity chemicals and advanced pharmaceutical intermediates.

Review Article | | Nature

Synthetic biology involves the creation of biological systems for new applications by modifying and reassembling biological components. Two views are presented here on the best way to engineer these components so that they reliably generate organisms with desired traits.

News & Views | | Nature