De novo protein design—From new structures to programmable functions

Cell, Год журнала: 2024, Номер 187(3), С. 526 - 544

Опубликована: Фев. 1, 2024

Methods from artificial intelligence (AI) trained on large datasets of sequences and structures can now "write" proteins with new shapes molecular functions de novo, without starting found in nature. In this Perspective, I will discuss the state field novo protein design at juncture physics-based modeling approaches AI. New folds higher-order assemblies be designed considerable experimental success rates, difficult problems requiring tunable control over conformations precise shape complementarity for recognition are coming into reach. Emerging incorporate engineering principles-tunability, controllability, modularity-into process beginning. Exciting frontiers lie deconstructing cellular and, conversely, constructing synthetic signaling ground up. As methods improve, many more challenges unsolved.

Язык: Английский

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An atlas of protein homo-oligomerization across domains of life

Cell, Год журнала: 2024, Номер 187(4), С. 999 - 1010.e15

Опубликована: Фев. 1, 2024

Protein structures are essential to understanding cellular processes in molecular detail. While advances artificial intelligence revealed the tertiary structure of proteins at scale, their quaternary remains mostly unknown. We devise a scalable strategy based on AlphaFold2 predict homo-oligomeric assemblies across four proteomes spanning tree life. Our results suggest that approximately 45% an archaeal proteome and bacterial 20% two eukaryotic form homomers. predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, unveil hundreds homo-oligomer types, including three confirmed experimentally by determination. Integrating these datasets with omics information suggests majority known complexes symmetric. Finally, provide structural context for interpreting disease mutations reveal coiled-coil regions as major enablers evolution human. is applicable any organism provides comprehensive view homo-oligomerization proteomes.

Язык: Английский

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Blueprinting extendable nanomaterials with standardized protein blocks

Nature, Год журнала: 2024, Номер 627(8005), С. 898 - 904

Опубликована: Март 13, 2024

Abstract A wooden house frame consists of many different lumber pieces, but because the regularity these building blocks, structure can be designed using straightforward geometrical principles. The design multicomponent protein assemblies, in comparison, has been much more complex, largely owing to irregular shapes structures 1 . Here we describe extendable linear, curved and angled as well inter-block interactions, that conform specified geometric standards; assemblies blocks inherit their extendability regular interaction surfaces, enabling them expanded or contracted by varying number modules, reinforced with secondary struts. Using X-ray crystallography electron microscopy, validate nanomaterial designs ranging from simple polygonal circular oligomers concentrically nested, up large polyhedral nanocages unbounded straight ‘train track’ reconfigurable sizes geometries readily blueprinted. Because complexity sequence–structure relationships, it not previously possible build deliberate placement backbones onto a blank three-dimensional canvas; simplicity our platform now enables construction nanomaterials according ‘back an envelope’ architectural blueprints.

Язык: Английский

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Coiled-coil domains are sufficient to drive liquid-liquid phase separation in protein models

Biophysical Journal, Год журнала: 2024, Номер 123(6), С. 703 - 717

Опубликована: Фев. 15, 2024

Язык: Английский

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Rationally seeded computational protein design of ɑ-helical barrels

Nature Chemical Biology, Год журнала: 2024, Номер 20(8), С. 991 - 999

Опубликована: Июнь 20, 2024

Abstract Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to two families of α-helical barrel proteins with central channels that bind small molecules. designs are seeded by the sequences structures defined de novo oligomeric barrel-forming peptides, adjacent helices connected loop building. For targets helices, short loops sufficient. However, require longer connectors; namely, an outer layer helix–turn–helix–turn–helix motifs packed onto barrels. Throughout these computational pipelines, residues define open states barrels maintained. This minimizes sequence sampling, accelerating process. each six targets, just synthetic genes made for expression in Escherichia coli . On average, 70% express give soluble monomeric fully characterized, including high-resolution most match models high accuracy.

Язык: Английский

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Diversity of Bioinspired Hydrogels: From Structure to Applications

Gels, Год журнала: 2023, Номер 9(5), С. 376 - 376

Опубликована: Май 2, 2023

Hydrogels are three-dimensional networks with a variety of structures and functions that have remarkable ability to absorb huge amounts water or biological fluids. They can incorporate active compounds release them in controlled manner. also be designed sensitive external stimuli: temperature, pH, ionic strength, electrical magnetic stimuli, specific molecules, etc. Alternative methods for the development various hydrogels been outlined literature over time. Some toxic therefore avoided when obtaining biomaterials, pharmaceuticals, therapeutic products. Nature is permanent source inspiration new functionalities more competitive materials. Natural present series physico-chemical characteristics suitable such as biocompatibility, antimicrobial properties, biodegradability, nontoxicity. Thus, they generate microenvironments comparable intracellular extracellular matrices human body. This paper discusses main advantages presence biomolecules (polysaccharides, proteins, polypeptides) hydrogels. Structural aspects induced by natural their properties emphasized. The most applications will highlighted, including drug delivery, self-healing materials regenerative medicine, cell culture, wound dressings, 3D bioprinting, foods,

Язык: Английский

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An atlas of protein homo-oligomerization across domains of life

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Июнь 11, 2023

Abstract Protein structures are essential to understand cellular processes in molecular detail. While advances AI revealed the tertiary structure of proteins at scale, their quaternary remains mostly unknown. Here, we describe a scalable strategy based on AlphaFold2 predict homo-oligomeric assemblies across four proteomes spanning tree life. We find that 50% archaeal, 45% bacterial, and 20% eukaryotic form homomers. Our predictions accurately capture protein homo-oligomerization, recapitulate megadalton complexes, unveil hundreds novel homo-oligomer types. Analyzing these datasets reveals coiled-coil regions as major enablers evolution Eukaryotes. Integrating with omics data shows majority known complexes symmetric. Finally, provide structural context for interpreting disease mutations, which enriched interfaces. is applicable any organism provides comprehensive view homo-oligomerization proteomes, networks, disease. Figure

Язык: Английский

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A de novo designed coiled coil-based switch regulates the microtubule motor kinesin-1

Nature Chemical Biology, Год журнала: 2024, Номер 20(7), С. 916 - 923

Опубликована: Июнь 7, 2024

Abstract Many enzymes are allosterically regulated via conformational change; however, our ability to manipulate these structural changes and control function is limited. Here we install a switch for allosteric activation into the kinesin-1 microtubule motor in vitro cells. Kinesin-1 heterotetramer that accesses open active closed autoinhibited states. The equilibrium between states centers on flexible elbow within complex coiled-coil architecture. We target engineer state can be opened with de novo designed peptide. alternative modeled computationally confirmed by biophysical measurements electron microscopy. In cells, peptide-driven increases kinesin transport, demonstrating primary role switching regulating activity. designs enabled understanding of ubiquitous structures, opening possibilities controlling other protein activities.

Язык: Английский

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CoCoNat: a novel method based on deep learning for coiled-coil prediction

Bioinformatics, Год журнала: 2023, Номер 39(8)

Опубликована: Авг. 1, 2023

Coiled-coil domains (CCD) are widespread in all organisms and perform several crucial functions. Given their relevance, the computational detection of CCD is very important for protein functional annotation. State-of-the-art prediction methods include precise identification boundaries, annotation typical heptad repeat pattern along coiled-coil helices as well oligomerization state.In this article, we describe CoCoNat, a novel method predicting helix residue-level register annotation, state. Our encodes sequences with combination two state-of-the-art language models implements three-step deep learning procedure concatenated Grammatical-Restrained Hidden Conditional Random Field refinement. A final neural network predicts When tested on blind test set routinely adopted, CoCoNat obtains performance superior to current both segment-level CCD. significantly outperforms most recent states.CoCoNat web server available at https://coconat.biocomp.unibo.it. Standalone version GitHub https://github.com/BolognaBiocomp/coconat.

Язык: Английский

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Design of Functional Globular β‐Sheet Miniproteins

ChemBioChem, Год журнала: 2024, Номер 25(7)

Опубликована: Янв. 26, 2024

The design of discrete β-sheet peptides is far less advanced than e. g. the α-helical peptides. reputation as being poorly soluble and aggregation-prone often hinders active efforts. Here, we show that this unfounded. We demonstrate by looking at β-hairpin WW domain. Their structure folding have been extensively studied they long served model systems to investigate protein kinetics. resulting fundamental understanding has led development hyperstable scaffolds fold temperatures 100 °C or high concentrations denaturants. These used functional miniproteins with nucleic acid binding properties, in some cases such success medical applications are conceivable. not always completely rigid, but can be specifically designed respond changes pH, redox potential presence metal ions. Some engineered also exhibit catalytic although comparable those natural proteins. Previous reviews focused on stably folded non-aggregating sequences. In our review, now address strategies obtain from motifs.

Язык: Английский

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