The de novo design of a protein capable of binding a cofactor in a unique orientation is a challenging problem because a range of structurally similar, yet different, complexes are often formed. Now, a team led by David N. Beratan, Michael J. Therien and William F. DeGrado report a protein — designed entirely from first principles — that binds a small-molecule cofactor in a unique and precisely predetermined orientation (shown schematically on the cover). Solving this puzzle required the design of a remote protein core that predisposes a flexible binding site to accommodate the porphyrin cofactor in a unique binding geometry.Article p1157IMAGE: NICHOLAS POLIZZICOVER DESIGN: TULSI VORALIA

Both the topology and the properties of woven materials have inspired researchers to explore their molecular counterparts, but it is challenging to weave at such small scales. Now, a team led by Helma Wennemers have devised a staple-shaped organic building block – with a rigid oligoproline segment in the middle and perylene–monoimide groups at each end – that self-assembles into a triaxial weave (shown schematically on the cover). The ends of the threads stack through π–π interactions to form linear chains with alternating up- and down-facing voids, which in turn serve as crossing points that hold the threads together in the woven structure through CH–π interactions. Article p1068; News & Views p1037

IMAGE: ILDAR BAYAZITOV AND ELLA MARUSHCHENKO (ELLA MARU STUDIO, INC.) COVER DESIGN: TULSI VORALIA

Tubingensin B is an indole diterpenoid that has a synthetically challenging chemical structure. Michael Corsello, Junyong Kim and Neil Garg from the University of California, Los Angeles, now report the total synthesis of this bioactive natural product. Their approach relies on the strategic use of a transient aryne intermediate — an aromatic ring containing a strained triple bond — to construct tubingensin B's pentacyclic core and highlights the utility of such long-avoided intermediates for the assembly of challenging structural motifs. The natural product's structure — underscored by the use of aryne intermediates in its synthesis — is stylized on the cover.Article p944IMAGE: DANIEL CASPI, ELEMENT TWENTYSIX

Rational catalyst design requires an understanding of how the size and electronic properties of ligands contribute to a complex's rate of catalysis. Although noble metals like palladium have benefitted from a large pool of data in this regard, base metals such as titanium and chromium have proven difficult to model. In an Article in this issue, Aaron Odom and co-workers describe a method for modelling high-valent transition metals that allows one to anticipate rate constants for new catalysts based on readily acquired parameters, as stylized on the cover.Article p837News & Views p834IMAGE: MATTHEW BOHAN ILLUSTRATION AND ANIMATIONCOVER DESIGN: TULSI VORALIA

Linear polymers with metals in the main chain have potential as molecular wires and can exhibit interesting magnetic and electronic properties. Polymetallocenes are a particularly promising class of metallopolymer, but are typically static in nature because of strong metal-ligand bonding. Now, Ian Manners and co-workers have shown that polymers based on nickelocene are dynamic as a consequence of relatively weak nickel-cyclopentadienyl interactions. Although static behaviour is observed on short timescales, chain-scission events lead to dynamic properties over long periods of time and the polynickelocenes can be readily depolymerized and repolymerized (as illustrated conceptually on the cover) which may ultimately prove useful for applications in data storage and retrieval.Article p743IMAGE: REBECCA MUSGRAVE AND SAM MUSGRAVECOVER DESIGN: TULSI VORALIA

Catalysis in biological systems typically involves the careful orchestration of supramolecular interactions within and between large biomolecules to control the spatial and temporal outcome of the reactions. Harnessing such cooperativity is challenging in synthetic macromolecular systems, but now a team led by Yao Lin and Jianjun Cheng have shown that brush polymers in which polypeptide chains are grown from a polynorbornene backbone can catalyse their own formation. The growing polypeptides can fold into α-helices (as stylized on the cover) which results in cooperative interactions between the macrodipoles of neighbouring chains and enhances the rate of their formation.Article p614IMAGE: AARON KAPPERCOVER DESIGN: TULSI VORALIA

Membraneless organelles formed through the phase separation of disordered proteins are involved in a variety of cellular functions. However, our understanding of the requirements for forming analogous artificial multi-component structures is limited. A team led by Nick J. Carroll and Gabriel P. López has now outlined some of the design rules for forming diverse assemblies through the phase separation of intrinsically disordered proteins within droplet microenvironments. The cover of this issue features a stylized image of a multi-layered coacervate, with each layer formed from a different protein phase.Article p509IMAGE: ELLA MARU STUDIOCOVER DESIGN: TULSI VORALIA

Cell membranes are a crucial component of biological systems and they fulfil a variety of essential roles, including the compartmentalization of chemical reactions as well as enabling the formation of concentration gradients. Molecules and ions, acting as chemical signals, must be transported across cell membranes to mediate a range of cellular functions. A collection of articles in this issue discuss artificial methods for transporting chemical information across lipid bilayers. The cover image shows a synthetic transmembrane pore — formed by the self-assembly of a-helical peptides — developed by a team led by Haganâ Bayley and Derek N. Woolfson and described on page 411.

Editorial p403; News & Views p406; Articles p411, p420, p426 and p431

IMAGE: LINGBING KONG

COVER DESIGN: SAMANTHA WHITHAM

Although we may never be able to say for sure what chemical and physical processes combined to produce the first living systems, advances in many different areas of contemporary research such as synthesis, physical chemistry and biochemistry — may offer some clues about our primordial past. A collection of Articles in this issue explore the origins of RNA and the small molecules related to the biological processes in which it is involved in order to provide new insights into the composition of early Earth and how life might have first emerged on it. The cover depicts a stylized representation of RNA replication on early Earth, with nucleotide binding mediated by a geophysical cycle (for example, day/night or seasons) as described in the Article by Hud and co-workers on page 318.p297p303p310p318p325IMAGE: CHRISTINE HE, GEORGIA INSTITUTE OF TECHNOLOGYCOVER DESIGN: KAREN MOORE

Although thermodynamic-based methods such as molecular docking have been very effective in the virtual screening of drug candidates, new approaches that will improve the success rate of computer-aided, structure-based drug design are still sought. Xavier Barril and colleagues have now developed a screening method based on structural — rather than thermodynamic — stability that is complementary to existing methods. Their approach uses dynamic undocking (DUck): a fast computational method to calculate the work necessary to break the most important contact with the receptor. The potential of the combination of docking and undocking strategies is demonstrated by screening a diverse set of molecules against the molecular chaperone and oncology target Hsp90 (as stylized on the cover).Article p201IMAGE: SERGIO RUIZ-CARMONA, UNIVERSITY OF BARCELONACOVER DESIGN: LAUREN HESLOP

Although scientists are able to reproduce many structural aspects of cellular compartmentalization found in biology, achieving mimicry of their social behaviours is somewhat more challenging. Now, Stephen Mann and co-workers have prepared a community of synthetic cell-like bodies, or protocells, in which ‘killer’ coacervate microdroplets (stylized on the cover in blue) target a population of proteinosomes (orange), lysing their membrane and capturing their payload. This research not only provides insight to how precursors to early cellular life may have operated, but also delivers a possible platform for new technologies.Article p110News & Views p107IMAGE: DR YAN QIAO, UNIVERSITY OF BRISTOLCOVER DESIGN: KAREN MOORE

Chiral recognition is a useful means of endowing molecules with directional binding interactions and can be used to control the modular construction of larger assemblies. Andrew I. Cooper, Graeme M. Day and co-workers have now adopted this strategy to show that porous organic cages can be packed together in a rational manner to form porous 1D nanotubes and pillared 3D frameworks (as stylized on the cover). This design principle thus permits the synthesis of reticular networks from purely organic molecules. Article p17; News & Views p6 IMAGE: ADAM KEWLEY, UNIVERSITY OF CAMBRIDGE COVER DESIGN: NADIA NELSON