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Bioorthogonal chemistry approaches have traditionally focused on selective ligation reactions between compatible reactive groups. This Perspective highlights progress in developing bioorthogonal cleavage reactions for diverse applications in chemical biology. Bioorthogonal chemical reactions are a thriving area of chemical research in recent years as an unprecedented technique to dissect native biological processes through chemistry-enabled strategies. However, current concepts of bioorthogonal chemistry have largely centered on 'bond formation' reactions between two mutually reactive bioorthogonal handles. Recently, in a reverse strategy, a collection of 'bond cleavage' reactions has emerged with excellent biocompatibility. These reactions have expanded our bioorthogonal chemistry repertoire, enabling an array of exciting new biological applications that range from the chemically controlled spatial and temporal activation of intracellular proteins and small-molecule drugs to the direct manipulation of intact cells under physiological conditions. Here we highlight the development and applications of these bioorthogonal cleavage reactions. Furthermore, we lay out challenges and propose future directions along this appealing avenue of research.

Bioorthogonal chemistry allows a wide variety of biomolecules to be specifically labeled and probed in living cells and whole organisms. Here we discuss the history of bioorthogonal reactions and some of the most interesting and important advances in the field.

In this Perspective, the authors advance a view of macromolecules as collections ofinterchanging structural ensembles, and discuss how a synergistic combination of NMR,X-ray crystallography, and computational simulations can reveal the structural basis for conformational dynamics at atomic resolution. Biomolecules adopt a dynamic ensemble of conformations, each with the potential to interact with binding partners or perform the chemical reactions required for a multitude of cellular functions. Recent advances in X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and other techniques are helping us realize the dream of seeing—in atomic detail—how different parts of biomolecules shift between functional substates using concerted motions. Integrative structural biology has advanced our understanding of the formation of large macromolecular complexes and how their components interact in assemblies by leveraging data from many low-resolution methods. Here, we review the growing opportunities for integrative, dynamic structural biology at the atomic scale, contending there is increasing synergistic potential between X-ray crystallography, NMR and computer simulations to reveal a structural basis for protein conformational dynamics at high resolution.

Chemical space — which encompasses all possible small organic molecules, including those present in biological systems — is vast. So vast, in fact, that so far only a tiny fraction of it has been explored. Nevertheless, these explorations have greatly enhanced our understanding of biology, and have led to the development of many of today's drugs. The discovery of new bioactive molecules, facilitated by a deeper understanding of the nature of the regions of chemical space that are relevant to biology, will advance our knowledge of biological processes and lead to new strategies to treat disease.

We asked a collection of chemical biologists, “What is the most exciting frontier area in chemical biology and what key technology is needed to advance knowledge and applications in this area?” and reveal some of the perspectives we received.

Introduction This Special Issue on “Thiophilic Metals: An ancient love for sulfur at the heart of biochemistry” has been compiled in celebration of the centenary of Bert Lester Vallee (1919–2010), a founding father and pioneer of zinc biochemistry, whose 100th birthday would have been on the 1st of June 2019. Interestingly, such a rounded approach of intentionally considering the person behind the scientist discloses additional sources and paves the way of presenting the biographies, for instance by sampling and citing from private letters, in which the persons themselves describe major events, or quoting public documents and petitions kept in local archives and the testimony of contemporaries. In his biography, which, as he himself would say in a moment of great excitement, is as hot as a “two barrel shotgun”, we shall combine information on his career, appointments, research interests, and achievements with his personal interests and journey from his birthplace, the German town of Hemer, to Boston, Massachusetts—a journey which, in turn, was embedded in and driven by the turbulences of the history of the 20th century. Besides Bertold, the couple had another son, Kurt Ziegbert, born in 1913 and father of a niece, Yona Kates, in Israel, and a nephew, Richard Bert Vallee, a professor at Columbia University in New York City.

Construction of a chemical system capable of replication and evolution, fed only by small molecule nutrients, is now conceivable. This could be achieved by stepwise integration of decades of work on the reconstitution of DNA, RNA and protein syntheses from pure components. Such a minimal cell project would initially define the components sufficient for each subsystem, allow detailed kinetic analyses and lead to improved in vitro methods for synthesis of biopolymers, therapeutics and biosensors. Completion would yield a functionally and structurally understood self‐replicating biosystem. Safety concerns for synthetic life will be alleviated by extreme dependence on elaborate laboratory reagents and conditions for viability. Our proposed minimal genome is 113 kbp long and contains 151 genes. We detail building blocks already in place and major hurdles to overcome for completion.