De novo design of transmembrane fluorescence-activating proteins

Nature, Год журнала: 2025, Номер unknown

Опубликована: Фев. 19, 2025

Язык: Английский

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Atomic context-conditioned protein sequence design using LigandMPNN

Nature Methods, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Protein sequence design in the context of small molecules, nucleotides and metals is critical to enzyme small-molecule binder sensor design, but current state-of-the-art deep-learning-based methods are unable model nonprotein atoms molecules. Here we describe a protein method called LigandMPNN that explicitly models all components biomolecular systems. significantly outperforms Rosetta ProteinMPNN on native backbone recovery for residues interacting with molecules (63.3% versus 50.4% 50.5%), (50.5% 35.2% 34.0%) (77.5% 36.0% 40.6%). generates not only sequences also sidechain conformations allow detailed evaluation binding interactions. has been used over 100 experimentally validated DNA-binding proteins high affinity structural accuracy (as indicated by four X-ray crystal structures), redesign designs increased as much 100-fold. We anticipate will be widely useful designing new proteins, sensors enzymes.

Язык: Английский

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Sculpting conducting nanopore size and shape through de novo protein design

Science, Год журнала: 2024, Номер 385(6706), С. 282 - 288

Опубликована: Июль 18, 2024

Transmembrane β-barrels have considerable potential for a broad range of sensing applications. Current engineering approaches nanopore sensors are limited to naturally occurring channels, which provide suboptimal starting points. By contrast, de novo protein design can in principle create an unlimited number new nanopores with any desired properties. Here we describe general approach designing transmembrane β-barrel pores different diameters and pore geometries. Nuclear magnetic resonance crystallographic characterization show that the designs stably folded structures resembling those models. The distinct conductances correlate their diameter, ranging from 110 picosiemens (~0.5 nanometer diameter) 430 (~1.1 diameter). Our opens door custom sequencing

Язык: Английский

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Binding and sensing diverse small molecules using shape-complementary pseudocycles

Science, Год журнала: 2024, Номер 385(6706), С. 276 - 282

Опубликована: Июль 18, 2024

We describe an approach for designing high-affinity small molecule–binding proteins poised downstream sensing. use deep learning–generated pseudocycles with repeating structural units surrounding central binding pockets widely varying shapes that depend on the geometry and number of repeat units. dock molecules interest into most shape complementary these pseudocycles, design interaction surfaces high affinity, experimentally screen to identify designs highest affinity. obtain binders four diverse molecules, including polar flexible methotrexate thyroxine. Taking advantage modular structure pockets, we construct chemically induced dimerization systems low-noise nanopore sensors by splitting domains reassemble upon ligand addition.

Язык: Английский

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Computational protein design

Nature Reviews Methods Primers, Год журнала: 2025, Номер 5(1)

Опубликована: Фев. 27, 2025

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Protein-induced membrane asymmetry modulates OMP folding kinetics and stability

Faraday Discussions, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Biological membranes are asymmetric structures, with asymmetry arising from differences in lipid identity each leaflet of the bilayer, as well non-uniform distribution lipids and small molecules membrane. Proteins can also induce modulate membrane based on their shape, sequence interactions lipids. How affects macromolecular behaviour is poorly understood because complexity natural systems, difficulties creating relevant bilayer systems vitro. Here, we present a method exploiting efficient, unidirectional folding transmembrane β-barrel outer protein, OmpA, to create proteoliposomes protein-induced dipoles known direction (arising variation engineered into OmpA loops). We then characterise kinetics stability different variants these proteoliposomes. find that both primary dipole which occurs play an important role for modulating rate folding. Critically, by complementarily matching charge protein it possible enhance folded OmpA. The results hint at how cells might exploit loop membrane-embedded proteins manipulate environments adaptation survival.

Язык: Английский

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Emergence of binding and catalysis from a designed generalist binding protein

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 31, 2025

Abstract The evolution of proteins that bind to small molecules and catalyze chemical transformations played a central role in the emergence life. While natural have finely tuned affinity for their primary ligands, they also often weak affinities other molecules. These interactions serve as starting points new specificities functions. Inspired by this concept, we determined ability simple de novo protein set diverse (< 300 Da) crystallographic fragment screening. We then used information design one variant binds fluorogenic molecule another acts highly efficient Kemp eliminase enzyme. Collectively, our work illuminates how novel functions can emerge from existing proteins.

Язык: Английский

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Whither the protein landscape?

Structural Dynamics, Год журнала: 2025, Номер 12(1)

Опубликована: Янв. 1, 2025

Язык: Английский

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Artificial intelligence in de novo protein design

Medicine in Novel Technology and Devices, Год журнала: 2025, Номер unknown, С. 100366 - 100366

Опубликована: Апрель 1, 2025

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Molecular circuits for genomic recording of cellular events

Trends in Genetics, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

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