Biochemistry articles within Nature Chemistry

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  • In Your Element |

    Madison Knapp and Jennifer Bridwell-Rabb explore the functions of chlorophyll and explain how our understanding of this green pigment has changed over time.

    • Madison Knapp
    •  & Jennifer Bridwell-Rabb

  • News & Views |

    Quantitatively studying the partitioning of biomolecules and reaction equilibria in cellular systems is an enormous challenge. Now, a multiphase coacervate model system provides insight into this complex biological problem, illustrating how coexisting phases influence RNA partitioning and duplex dissociation.

    • Shuqi Wu
    •  & Liangfei Tian

  • Article |

    The β1-adrenergic receptor (β1AR) contains empty cavities in its preactive conformation, which disappear in the active one. Now, using X-ray crystallography of xenon-derivatized β1AR crystals, a cavity has been shown to be in contact with the cholesterol-binding pocket. Monitoring the binding of a cholesterol analogue in solution has explained the function of cholesterol as a negative allosteric modulator of β1AR.

    • Layara Akemi Abiko
    • , Raphael Dias Teixeira
    •  & Stephan Grzesiek

  • Article
    | Open Access

    Most proteins must fold co-translationally on the ribosome to adopt biologically active conformations, yet structural, mechanistic descriptions are lacking. Using 19F NMR spectroscopy to study a nascent multi-domain protein has now enabled the identification of two co-translational folding intermediates that are significantly more stable than intermediates formed off the ribosome, suggesting that the ribosome may thermodynamically regulate folding.

    • Sammy H. S. Chan
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Perspective |

    Droplet interface bilayers (DIBs) are a type of artificial bilayer that can act as cell membrane mimics. This Perspective surveys how DIBs can be used to mimic key cellular features (such as bilayer asymmetry) and processes (such as drug movement), and discusses challenges that need to be overcome to enable DIBs to reach their full potential as biomimetic model membranes.

    • Elanna B. Stephenson
    • , Jaime L. Korner
    •  & Katherine S. Elvira

  • Article |

    Metal-free amyloid-β (Aβ) and metal-bound Aβ (metal–Aβ) are found in the brain of patients with Alzheimer’s disease. Now, it has been shown that the conformation of a native neuropeptide, somatostatin, is changed in the presence of copper ions, Aβ and metal–Aβ. The conformational change results in a loss of function of somatostatin as a neurotransmitter and a gain of function as a modulator against metal–Aβ.

    • Jiyeon Han
    • , Jiwon Yoon
    •  & Mi Hee Lim

  • Article
    | Open Access

    Analogues of mRNA 5′ caps containing a photo-cleavable group have now been developed. These so-called FlashCaps can be used for routine in vitro transcription to make long mRNAs containing a cap. In cells, the capped mRNAs are translationally muted; however, upon irradiation by light, the photo-cleavable group is removed without leaving any remaining modification and mRNA is then translated into the corresponding protein.

    • Nils Klöcker
    • , Florian P. Weissenboeck
    •  & Andrea Rentmeister

  • Article
    | Open Access

    Phytochromes regulate plant growth by sensing far-red light through the photoisomerization of their protein-bound chromophores. In the phytochrome Agp2, it has now been demonstrated that ultrafast proton-transfer occurs from the chromophore to a protein–water network before photoisomerization, inducing protein changes on the ultrafast timescale. These protein changes develop further on longer timescales, resulting in an activated protein conformation.

    • Yang Yang
    • , Till Stensitzki
    •  & Karsten Heyne

  • Article |

    A reduction reaction is usually equated with an electron transfer reaction. Now, ultrafast time-resolved serial femtosecond X-ray crystallography has enabled the visualization of the stepwise structural changes that occur after electron transfers have been observed in the light-triggered reduction of flavin adenine dinucleotide catalysed by DNA photolyase.

    • Manuel Maestre-Reyna
    • , Cheng-Han Yang
    •  & Ming-Daw Tsai

  • In Your Element |

    Christine M. Le takes a look at 2-[18F]fluoro-2-deoxyglucose and explains how this radioactive sugar could help to save your life.

    • Christine M. Le

  • Article |

    Carbonic anhydrase enzymatically catalyses CO2 hydration, and its effect on enzymatic and heterogeneous CO2 reduction has now been studied. Through the co-immobilization of carbonic anhydrase, it has been shown that faster CO2 hydration kinetics are beneficial for enzymatic catalysis (using formate dehydrogenase) but detrimental for heterogeneous catalysts, such as gold.

    • Samuel J. Cobb
    • , Vivek M. Badiani
    •  & Erwin Reisner

  • Review Article |

    Viruses use the cellular machinery of their host organism to reproduce. This Review discusses how [FeS] cluster-containing proteins activate, support and modulate the innate immune response to restrict viral infections as well as highlighting how some of these proteins simultaneously support the replication of viruses.

    • Kourosh Honarmand Ebrahimi
    • , Simone Ciofi-Baffoni
    •  & Fraser A. Armstrong

  • Article
    | Open Access

    Phase-separated compartments have long been proposed as precursors to cellular life. Now, it has been shown that RNA–peptide protocells are more robust when formed using shorter (rather than longer) peptides, and that peptide sequence determines the functional materials properties of these compartments.

    • Juan M. Iglesias-Artola
    • , Björn Drobot
    •  & Moritz Kreysing

  • In Your Element |

    Amina Schartup relates how our understanding of methylmercury has changed in the 170 years since it was discovered — as well as some of the disasters that occurred along the way.

    • Amina T. Schartup

  • Article |

    Histone H1 binds to nucleosomes with ultrahigh affinity, implying residence times incompatible with efficient biological regulation. Now it has been shown that the disordered regions of H1 retain their large-amplitude dynamics on the nucleosome, which enables a charged disordered histone chaperone to invade the H1–nucleosome complex and vastly accelerate H1 dissociation.

    • Pétur O. Heidarsson
    • , Davide Mercadante
    •  & Benjamin Schuler

  • Article |

    The complex link between protein sequence and phase behaviour for a family of prion-like low-complexity domains (PLCDs) has now been revealed. The results have uncovered a set of rules—which are interpreted using a stickers-and-spacers model—that govern the sequence-encoded phase behaviour of such PLCDs and enable physicochemical rationalizations that are connected to the underlying sequence composition.

    • Anne Bremer
    • , Mina Farag
    •  & Tanja Mittag

  • Article |

    Directed evolution of a primitive computationally designed enzyme has produced an efficient and enantioselective biocatalyst for the Morita–Baylis–Hillman reaction. The engineered enzyme uses a designed histidine nucleophile operating in synergy with a catalytic arginine that emerged during evolution and serves as a genetically encoded surrogate of privileged bidentate hydrogen-bonding catalysts.

    • Rebecca Crawshaw
    • , Amy E. Crossley
    •  & Anthony P. Green

  • Article |

    The systemic discovery of metal–small-molecule complexes from biological samples is a difficult challenge. Now, a method based on liquid chromatography and native electrospray ionization mass spectrometry has been developed. The approach uses post-column pH adjustment and metal infusion combined with ion identity molecular networking, and a rule-based informatics workflow, to interrogate small-molecule–metal binding.

    • Allegra T. Aron
    • , Daniel Petras
    •  & Pieter C. Dorrestein

  • Article |

    An integrated multiprotein nanopore has been fabricated using components from all three domains of life. This molecular machine opens the door to two approaches in single-molecule protein analysis, in which selected substrate proteins are unfolded, fed to into the proteasomal chamber and then processed either as fragmented peptides or intact polypeptides.

    • Shengli Zhang
    • , Gang Huang
    •  & Giovanni Maglia

  • Article |

    Biosynthesis of aromatic amines typically uses glutamic acid or glutamine as the nitrogen donor. Now, a biosynthetic pathway to aromatic amines has been reported that uses glycyl-tRNA as the nitrogen donor. The myosin-targeting ammosamide is made via a pathway that involves the post-translational modification of a tryptophan, which is added to the end of a peptide in a tryptophanyl-tRNA-dependent step.

    • Page N. Daniels
    • , Hyunji Lee
    •  & Wilfred A. van der Donk

  • Thesis |

    Bruce C. Gibb reminds us that buffers are not necessarily innocent bystanders and that they can bind to biomacromolecules too.

    • Bruce C. Gibb

  • Article |

    Self-propelled artificial chemical swimmers have previously been developed for chemical sensing. Now, hybrid bioelectrochemical swimmers, capable of translating chiral molecular information into macroscopic motion, have been developed. Diastereomeric interactions between enantiopure oligomers immobilized on the swimmer and a chiral molecule present in solution control the trajectory of the device.

    • Serena Arnaboldi
    • , Gerardo Salinas
    •  & Alexander Kuhn

  • Article
    | Open Access

    During polypeptide biosynthesis, a strong interaction can occur between a segment of an emerged, disordered nascent protein and the ribosomal surface. Now, it has been shown that competition between this ribosomal binding and the folding energetics of an immunoglobulin-like domain modulates the mechanism of co-translational folding.

    • Anaïs M. E. Cassaignau
    • , Tomasz Włodarski
    •  & John Christodoulou

  • Article |

    Located in the catalytically important belt region, the ‘ninth sulfur’ of the nitrogenase cofactor has now been shown to be inserted through coordination of sulfite by two cluster iron atoms at a vacant belt site. This is followed by in situ reduction of sulfite to sulfide, which enables the subsequent transfer and functionalization of the cofactor.

    • Kazuki Tanifuji
    • , Andrew J. Jasniewski
    •  & Markus W. Ribbe

  • Article |

    Liquid–liquid phase separation plays an important role in creating cellular compartments and protocells, but designing small-molecule models remains difficult. A peptide-based synthon for liquid–liquid phase separation consisting of two stickers and a flexible, polar spacer has now been presented. Condensates formed by these synthons can concentrate biomolecules and catalyse anabolic reactions.

    • Manzar Abbas
    • , Wojciech P. Lipiński
    •  & Evan Spruijt

  • Article |

    Triphenylphosphonium ylides (Wittig reagents) that selectively react with sulfenic acids—a pivotal post-translational cysteine modification in redox biology—are developed. This bioconjugation method enables a site-specific proteome-wide stoichiometry analysis of S-sulfenylation, and visualization of redox-dependent changes in mitochondrial cysteine oxidation and the redox-triggered generation of triphenylphosphonium for the controlled delivery of small molecules to mitochondria.

    • Yunlong Shi
    • , Ling Fu
    •  & Kate S. Carroll

  • Article |

    The correct function of ribozymes in a prebiotic world would be dependent on the presence of optimal salt compositions and concentrations. Now, local heat fluxes have been shown to create an ideal salt habitat for ribozyme activity based on geologically plausible salt-leaching processes.

    • T. Matreux
    • , K. Le Vay
    •  & C. B. Mast

  • Article |

    The construction of mechanically interlocked molecules solely made from peptides is a great synthetic challenge because of a lack of effective templating strategies. Now it has been shown that by combining self-assembly and dynamic covalent chemistry, catenanes, daisy chains and other interlocked peptides can be synthesized from genetically engineered building blocks.

    • Hendrik V. Schröder
    • , Yi Zhang
    •  & A. James Link

  • Article |

    The opening mechanism of the SARS-CoV-2 spike protein has been studied by integrating computational and experimental data. Combining weighted ensemble molecular dynamics simulations, biolayer interferometry and ManifoldEM analysis of cryo-EM data revealed that the glycan at N343 plays a gating role in the opening mechanism of the SARS-CoV-2 spike protein.

    • Terra Sztain
    • , Surl-Hee Ahn
    •  & Rommie E. Amaro

  • Article |

    Computationally designed enzymes can be substantially improved by directed evolution. Now, it has been shown that evolution can introduce a dynamic network that selectively tightens the transition-state ensemble, giving rise to a negative activation heat capacity. Targeting such transition state conformational dynamics may expedite de novo enzyme creation.

    • H. Adrian Bunzel
    • , J. L. Ross Anderson
    •  & Adrian J. Mulholland

  • Article |

    Elucidating the origin of translation—the process that produces a specific peptide from an RNA sequence—is one of the most difficult challenges in prebiotic chemistry and evolutionary biology. Now, it has been shown that aminoacylated nucleotides couple to amino-acid-bearing oligoribonucleotides, directed by an RNA template, forming specific di- and tripeptides in the absence of ribosomal machinery.

    • Biswarup Jash
    • , Peter Tremmel
    •  & Clemens Richert

  • News & Views |

    Designing membrane proteins that function as ion channels is challenging. Now, peptides that self-assemble into water-soluble α-helical barrels have been repurposed to form ion channels in membranes by lining the interior with polar residues and the exterior with hydrophobic ones.

    • Giovanna Ghirlanda

  • Article |

    The molybdenum cofactor (Moco) is found in the active site of numerous enzymes, but the mechanism of molybdate insertion is not clear. Now, the mechanism of the final maturation step, in which adenylated molybdopterin and molybdate are the substrates, has been revealed. X-ray crystallography of an Mo-insertase identified adenylated Moco as an unexpected intermediate in this reaction sequence.

    • Corinna Probst
    • , Jing Yang
    •  & Tobias Kruse

  • Article |

    Zinc fluxes have now been shown to be essential in the fertilization of amphibian eggs. Furthermore, manganese(ii), which is initially bound to low-molecular-weight carboxylates, is stored and released with zinc from cortical vesicles following fertilization. This rapid metal ion release blocks the otherwise fatal entry of a second sperm.

    • John F. Seeler
    • , Ajay Sharma
    •  & Thomas V. O’Halloran

  • Article |

    Although iron–sulfur cofactors are known to carry out biological nitrogen fixation, how these clusters bind dinitrogen remains poorly understood. Now, a dinitrogen complex of a synthetic iron–sulfur cluster has been characterized, and electronic cooperation in the cluster has been shown to result in strong N–N bond activation.

    • Alex McSkimming
    •  & Daniel L. M. Suess

  • Article |

    Simulations of the SARS-CoV-2 proteome that include over 0.1 s of aggregate data are reported. Spike opening was observed, revealing cryptic epitopes that differ between variants, explaining differential interactions with antibodies and receptors that determine pathogenicity. The cryptic pockets described provide new targets for antivirals and a wealth of mechanistic insight.

    • Maxwell I. Zimmerman
    • , Justin R. Porter
    •  & Gregory R. Bowman

  • Article |

    RNA origami can be used for the modular design of RNA nanoscaffolds but can be challenging to design. Newly developed computer-aided design software has now been shown to improve the folding yield of kilobase-sized RNA origami. These structures fold from a single strand during transcription by an RNA polymerase, and are able to position small molecules and protein components with nanoscale precision.

    • Cody Geary
    • , Guido Grossi
    •  & Ebbe S. Andersen

  • Article |

    The de novo design of functional membrane proteins is a formidable challenge. Now, water-soluble peptides have been designed that assemble into α-helical barrels with accessible, polar and hydrated central channels. Insights from these structures have been used to produce stable membrane-spanning, cation-selective channels.

    • Alistair J. Scott
    • , Ai Niitsu
    •  & Derek N. Woolfson

  • News & Views |

    Harnessing the unique catalytic properties of enzymes for abiotic reactions is a prized goal that has inspired a variety of approaches in enzyme design and engineering. Now, the transfer hydrogenation of ketones with silanes has been reported, catalysed by a native carbonic anhydrase.

    • Hans Martin Senn

  • Article |

    The post-translational modification O-GlcNAc on amyloid-forming proteins can inhibit their aggregation. Now, it has been shown that O-GlcNAc modification of small heat shock proteins HSP27, αA- and αB-crystallin can increase their anti-amyloid activity and block the amyloid formation of both α-synuclein and Aβ(1–42). A mechanism for this protective effect based on decreased physical interactions is also proposed.

    • Aaron T. Balana
    • , Paul M. Levine
    •  & Matthew R. Pratt

  • Article |

    Enzymatic reactions involving mononuclear metal hydrides are unknown in nature, despite the prevalence of such intermediates in synthetic transition-metal catalysed reactions. Now, it has been shown that zinc-containing carbonic anhydrase enzymes can catalyse hydride transfers from silanes to ketones with high enantioselectivity and there is evidence to support the intermediacy of a mononuclear zinc hydride.

    • Pengfei Ji
    • , Jeeyoung Park
    •  & John F. Hartwig

  • Article |

    High-throughput biocatalytic screening and metagenomics have been used to discover over 300 imine reductases (IREDs) and subsequently produce a sequence-diverse panel of IREDs suitable for optimizing the synthesis of chiral amines. Additional characterization identified biocatalysts that accommodate structurally demanding amines and ketones for enzymatic reductive aminations.

    • James R. Marshall
    • , Peiyuan Yao
    •  & Nicholas J. Turner

  • Article |

    Bacteria use thioester-bond-containing proteins to covalently bind to host surfaces and withstand large mechanical shocks. Now, thioester bond reactivity has been shown to be force-dependent: forces >35 pN inhibit bond cleavage by primary amine ligands, whereas forces <6 pN enable reversible reformation. This force-modulated thioester bond reactivity could potentially enable bacterial mobility and a route by which they optimize infection.

    • Alvaro Alonso-Caballero
    • , Daniel J. Echelman
    •  & Julio M. Fernandez

  • Review Article |

    Metabolic labelling with unnatural sugars can be used to selectively label tumours with chemical tags. These tags then enable the targeted delivery of molecular cargo including diagnostic and therapeutic agents. This Review Article discusses progress in the design and delivery of unnatural sugars for metabolic labelling of tumour cells and the subsequent development of tumour-targeted chemistry.

    • Hua Wang
    •  & David J. Mooney

  • Article |

    Despite the fundamental role of ATPase in catalysing ATP hydrolysis, the structural and energetic aspects of this process are not fully understood. Coarse-grained computational models have now been used to calculate the free-energy surfaces of different types of ATPases. The catalytic dwell is shown not to be crucial for movement against applied torque.

    • Chen Bai
    • , Mojgan Asadi
    •  & Arieh Warshel

  • Article |

    Latent functional groups—typically unreactive unless activated by protein binding—can provide additional selectivity to covalent drugs. Now, compounds containing the weakly electrophilic sulfuramidimidoyl fluoride group, capable of undergoing sulfur(vi) fluoride exchange, have been used to identify reactive proteins in human cell lysate. This approach has identified a compound that conjugates to and inhibits an important anticancer target.

    • Gabriel J. Brighty
    • , Rachel C. Botham
    •  & Jeffery W. Kelly

  • Article |

    A selection-based screen has now revealed preferences in small-molecule chemotypes that bind RNA as well as preferences in the RNA motifs that bind small molecules. Analysis of these data enabled the design of a small molecule that selectively binds a non-coding microRNA and upregulates expression of vascular endothelial growth factor A.

    • Hafeez S. Haniff
    • , Laurent Knerr
    •  & Matthew D. Disney

  • News & Views |

    An approach to design artificial intrinsically disordered proteins using a short peptide as a repeating unit has been reported. This design enables the phase behaviour of the protein to be finely tuned inside cells and enabled the formation of phase-separated condensates that can modulate chemical reactions.

    • Soumik Ray
    •  & Samir K. Maji

  • Article |

    A series of enzymes that catalyse the formation of strained peptide cyclophanes through a stereospecific C(sp2)–C(sp3) bond have been identified. Crosslinking occurs on three-residue motifs that include tryptophan or phenylalanine to form indole- or phenyl-bridged cyclophanes. These enzymes are widely distributed in nature and represent promising tools for peptide biotechnology.

    • Thi Quynh Ngoc Nguyen
    • , Yi Wei Tooh
    •  & Brandon I. Morinaka

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