Protein design articles within Nature Communications

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  • Article
    | Open Access

    Recent protein design methods rely on large neural networks, yet it is unclear which dependencies are critical for determining function. Here, authors show that learning the per residue mutation preferences, without considering interactions, enables design of functional and diverse protein variants.

    • David Ding
    • , Ada Y. Shaw
    •  & Debora S. Marks

  • Article
    | Open Access

    Conditional degradation of proteins is instrumental to advance our knowledge of cell biology but has been lacking for organelles like mitochondria. Here, the authors develop a proteolysis system based on the mycoplasma Lon protease that functions selectively within mitochondria in yeast and human cells.

    • Swastika Sanyal
    • , Anna Kouznetsova
    •  & Camilla Björkegren

  • Article
    | Open Access

    The authors present a generalisable computational approach to stabilize class I fusion proteins in the prefusion state. The method was used to stabilize the fusion proteins of RSV, hMPV, and SARS-CoV-2 viruses, with the designs structurally validated and RSV F protein assessed in a neutralization assay.

    • Karen J. Gonzalez
    • , Jiachen Huang
    •  & Eva-Maria Strauch

  • Article
    | Open Access

    In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.

    • Joseph Dodd-o
    • , Abhishek Roy
    •  & Vivek Kumar

  • Article
    | Open Access

    The ability to engineer novel protein structures has tremendous scientific and therapeutic impact. Here, authors develop a generative model acting upon an angular representation of protein structures to create high quality protein backbones.

    • Kevin E. Wu
    • , Kevin K. Yang
    •  & Ava P. Amini

  • Article
    | Open Access

    Cas13 systems suffer from a lack of spatiotemporal control. Here the authors report paCas13, a light-inducible Cas13 system created by fusing Magnet with fragment pairs; they also report padCas13, a light-inducible base-editing system by fusing ADAR2 to catalytically inactive paCas13 fragments.

    • Jeonghye Yu
    • , Jongpil Shin
    •  & Won Do Heo

  • Article
    | Open Access

    In contrast to their clinical success as inhibitors and targeting agents, antibodies have generally been ineffective as receptor agonists. Here, Romei et al. leverage a natural homotypic interface to tune antibody geometry, enabling optimization of agonist activity for multiple therapeutic targets.

    • Matthew G. Romei
    • , Brandon Leonard
    •  & Greg A. Lazar

  • Article
    | Open Access

    Screening mutated proteins is a versatile strategy in protein research, producing massive datasets when combined with NGS. Here, authors present ACIDES to estimate mutated protein fitness and aid protein engineering pipelines in a range of applications, including gene therapy.

    • Takahiro Nemoto
    • , Tommaso Ocari
    •  & Ulisse Ferrari

  • Article
    | Open Access

    Most proteins mediating biomineralization in nature are not well structured, and the structures of the relevant protein-mineral interfaces regulating mineralization are elusive. Here, the authors computationally design proteins that modulate calcium carbonate mineralization to generate hybrid materials and elucidate the roles of designed proteins in controlling mineralization.

    • Fatima A. Davila-Hernandez
    • , Biao Jin
    •  & David Baker

  • Article
    | Open Access

    Predicting the effective assembly of a set of proteins into a desired structure has traditionally been a challenging task. Here, authors demonstrate that advancements in automatic differentiation make it possible to address this problem using classical statistical mechanics.

    • Agnese I. Curatolo
    • , Ofer Kimchi
    •  & Michael P. Brenner

  • Article
    | Open Access

    Prediction of enzyme kinetic parameters is essential for designing and optimising enzymes for various biotechnological and industrial applications. Here, authors presented a prediction framework (UniKP), which improves the accuracy of predictions for three enzyme kinetic parameters.

    • Han Yu
    • , Huaxiang Deng
    •  & Xiaozhou Luo

  • Article
    | Open Access

    Membraneless liquid compartments based on phase-separating biopolymers have been observed in diverse cell types and attributed to weak multivalent interactions predominantly based on intrinsically disordered domains. Here the authors design protein liquid condensates from tunable concatenated coiled-coil dimer modules, unraveling the principles for coexisting condensates, chemical regulation, formation from either one or two polypeptide components in mammalian cells.

    • Maruša Ramšak
    • , Dominique A. Ramirez
    •  & Roman Jerala

  • Article
    | Open Access

    A pan-betacoronavirus vaccine will likely require the elicitation of antibodies against spike regions conserved across diverse coronaviruses. Here, authors computationally engineer and experimentally validate immunogens to elicit antibodies against two such spike regions.

    • A. Brenda Kapingidza
    • , Daniel J. Marston
    •  & Mihai L. Azoitei

  • Article
    | Open Access

    High binding affinities are usually obtained when ligands are rigidified. Here the authors present flexible peptides binding to Armadillo repeat proteins with femtomolar affinity. They demonstrate that the bound state is characterized by residual dynamics limiting entropic losses upon binding.

    • Stefano Cucuzza
    • , Malgorzata Sitnik
    •  & Oliver Zerbe

  • Article
    | Open Access

    Genetic code expansion (GCE) is a protein engineering tool that enables programmed and site-specific installation of noncanonical amino acids into proteins. Here, authors show that cellular stress remodelling boosts GCE in mammalian cells including GCE realized by orthogonally translating organelles.

    • Mikhail E. Sushkin
    • , Christine Koehler
    •  & Edward A. Lemke

  • Article
    | Open Access

    l-Lactate is increasingly recognized as a key metabolite and signalling molecule in mammals, but the methods to investigate it in vivo have been limited. Here, authors report a pair of improved biosensors—one green and one red—for visualizing l-lactate both inside and outside of cells.

    • Yusuke Nasu
    • , Abhi Aggarwal
    •  & Robert E. Campbell

  • Article
    | Open Access

    This study reports the successful de novo design of a trefoil knotted protein fold for which the crystal structure agrees closely with the intended trefoil knot topology.

    • Lindsey A. Doyle
    • , Brittany Takushi
    •  & Philip Bradley

  • Article
    | Open Access

    Tools for high spatiotemporal control of cell-cell adhesions are lacking. Here, authors propose an optogenetic tool, opto-E-cadherin, that allows reversible control of E-cadherin-mediated cell-cell adhesions with blue light.

    • Brice Nzigou Mombo
    • , Brent M. Bijonowski
    •  & Seraphine V. Wegner

  • Article
    | Open Access

    The study of interstitial calcium remains challenging due to scarce methodology. Here, authors present ultra-low affinity genetically encoded fluorescent biosensors for monitoring calcium in intercellular spaces in living tissues.

    • Ariel A. Valiente-Gabioud
    • , Inés Garteizgogeascoa Suñer
    •  & Oliver Griesbeck

  • Article
    | Open Access

    Most current anti-coronavirus nanoparticle vaccines target epitopes within the RBD. Here, the authors developed nanoparticles displaying an array of spike fusion proteins derived from various coronaviruses and show that immunizing mice with these vaccines elicits broad and potent cross-reactive antibodies.

    • Geoffrey B. Hutchinson
    • , Olubukola M. Abiona
    •  & Kizzmekia S. Corbett-Helaire

  • Article
    | Open Access

    The ability to rationally remodel enzyme conformational landscapes to modify catalytic properties is limited. Here, the authors, using a computational procedure, redesign the conformational landscape of an aminotransferase to stabilize a less populated but reactive conformation and thereby increase catalytic efficiency with a non-native substrate.

    • Antony D. St-Jacques
    • , Joshua M. Rodriguez
    •  & Roberto A. Chica

  • Article
    | Open Access

    Roy et al. describe a generalized method for computationally designing miniproteins selective for a single integrin heterodimer and conformational state. The designed αvβ6 inhibitor remains monomeric and maintains biological activity following aerosolization and shows excellent efficacy in bleomycin induced lung fibrosis.

    • Anindya Roy
    • , Lei Shi
    •  & David Baker

  • Article
    | Open Access

    Here the authors use structure-based design to engineer a single component immunogen that mimics the malaria parasite AMA1-RON2 complex required for invasion of host cells, and show that it elicits a potent strain-transcending antibody response in rats.

    • Palak N. Patel
    • , Thayne H. Dickey
    •  & Niraj H. Tolia

  • Article
    | Open Access

    New delivery platforms are needed to allow broader application of biotherapeutics for CNS diseases. Here, the authors show enhanced CNS delivery with a transport vehicle engineered to bind CD98hc, a highly expressed target at the blood-brain barrier.

    • Kylie S. Chew
    • , Robert C. Wells
    •  & Mihalis S. Kariolis

  • Article
    | Open Access

    Conformational cooperativity is a universal molecular effect mechanism and plays a critical role in signalling pathways. Here the authors present a programmable conformational cooperativity strategy to construct the oligo-protein signal transduction platform for logic operations and gene regulations which can be cooperatively regulated by conformational signals.

    • Yuan Liang
    • , Yunkai Qie
    •  & Cheng Zhang

  • Article
    | Open Access

    Extensive research efforts have been directed towards the development of PET hydrolases with improved activity, but template enzymes used are limited. Here, the authors report a PET hydrolase from Cryptosporangium aurantiacum (CaPETase) that exhibits high thermostability and PET degradation activity at ambient temperatures and determine its crystal structure.

    • Hwaseok Hong
    • , Dongwoo Ki
    •  & Kyung-Jin Kim

  • Article
    | Open Access

    Nonalcoholic steatohepatitis (NASH) starts with lipid droplet accumulation in the liver that eventually causes inflammation and fibrosis. Here, authors use lipophagy activators to limit the accumulation of lipids in the liver and show that this can prevent disease progression in a mouse model of nonalcoholic steatohepatitis.

    • Yoshito Minami
    • , Atsushi Hoshino
    •  & Satoaki Matoba

  • Article
    | Open Access

    Endonucleases play crucial roles in various biological processes but endonucleases that target small non-coding RNAs have not been reported. Here, the authors combined the metal binding non-canonical amino acid BpyAla and a high affinity binder to engineer a catalyst that degrades small non-coding RNAs.

    • Noreen Ahmed
    • , Nadine Ahmed
    •  & John Paul Pezacki

  • Article
    | Open Access

    Natural proteins exhibit rich structural diversity based on the folds of an invariably linear chain. Here the authors design a single-domain GFP catenane as the counterpart of conventional linear GFP with enhanced thermal resilience and to provide a robust scaffold for making fusion protein catenanes.

    • Zhiyu Qu
    • , Jing Fang
    •  & Wen-Bin Zhang

  • Article
    | Open Access

    Here, the authors develop a protein engineering method that enables high-resolution structural biology study of human fatty acid synthase. Using this technique, they uncover unique structural features of the enzyme and the mechanism of its inhibition by an anticancer drug Denifanstat.

    • S. M. Naimul Hasan
    • , Jennifer W. Lou
    •  & Mohammad T. Mazhab-Jafari

  • Article
    | Open Access

    Mutations in a protein active site can alter function in useful ways, but the active site is sensitive to changes. Here the authors present a general strategy to design combinatorial mutation libraries. Applied to GFP, the authors isolate thousands of fluorescent designs that exhibit large and useful changes in spectral properties.

    • Jonathan Yaacov Weinstein
    • , Carlos Martí-Gómez
    •  & Sarel J. Fleishman

  • Article
    | Open Access

    Engineering protein biosensors that respond to biomolecules by triggering cellular responses has largely relied on binding rigid molecules. Here, the authors develop a computational strategy for designing signaling complexes between conformationally dynamic proteins and peptides.

    • Robert E. Jefferson
    • , Aurélien Oggier
    •  & Patrick Barth

  • Article
    | Open Access

    Recently, a pipeline for the design of protein-binding proteins using only the structure of the target protein was reported. Here, the authors report that the incorporation of deep learning methods into the original pipeline increases experimental success rate by ten-fold.

    • Nathaniel R. Bennett
    • , Brian Coventry
    •  & David Baker

  • Article
    | Open Access

    Multi-enzymatic cascades benefit from precise nanometric organization but achieving this using available scaffolds is challenging. Here the authors present strategy for organizing multienzymatic systems using a protein scaffold based on TRAP domains, and demonstrate improved catalytic output.

    • Alba Ledesma-Fernandez
    • , Susana Velasco-Lozano
    •  & Aitziber L. Cortajarena

  • Review Article
    | Open Access

    Ebrahimi and Samanta review the key advances in the chemical and structural modification of proteins that have enabled their rise as indispensable tools in medicine and outline emerging protein engineering strategies that can potentially unlock structures with improved therapeutic properties.

    • Sasha B. Ebrahimi
    •  & Devleena Samanta

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