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- PDB-9exk: Scalable protein design using hallucination in a relaxed sequence... -

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Entry
Database: PDB / ID: 9exk
TitleScalable protein design using hallucination in a relaxed sequence space
ComponentsDe novo designed protein K12
KeywordsDE NOVO PROTEIN / De novo designed protein K12
Biological speciessynthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.36 Å
AuthorsFrank, C.J. / Dietz, H.
Funding supportEuropean Union, Germany, 2items
OrganizationGrant numberCountry
European Research Council (ERC)GA#101018465European Union
Germanys Excellence StrategyTUM Innovation Network Projekt RISE Germany
CitationJournal: Science / Year: 2024
Title: Scalable protein design using optimization in a relaxed sequence space.
Authors: Christopher Frank / Ali Khoshouei / Lara Fuβ / Dominik Schiwietz / Dominik Putz / Lara Weber / Zhixuan Zhao / Motoyuki Hattori / Shihao Feng / Yosta de Stigter / Sergey Ovchinnikov / Hendrik Dietz /
Abstract: Machine learning (ML)-based design approaches have advanced the field of de novo protein design, with diffusion-based generative methods increasingly dominating protein design pipelines. Here, we ...Machine learning (ML)-based design approaches have advanced the field of de novo protein design, with diffusion-based generative methods increasingly dominating protein design pipelines. Here, we report a "hallucination"-based protein design approach that functions in relaxed sequence space, enabling the efficient design of high-quality protein backbones over multiple scales and with broad scope of application without the need for any form of retraining. We experimentally produced and characterized more than 100 proteins. Three high-resolution crystal structures and two cryo-electron microscopy density maps of designed single-chain proteins comprising up to 1000 amino acids validate the accuracy of the method. Our pipeline can also be used to design synthetic protein-protein interactions, as validated experimentally by a set of protein heterodimers. Relaxed sequence optimization offers attractive performance with respect to designability, scope of applicability for different design problems, and scalability across protein sizes.
History
DepositionApr 8, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Data collection / Database references / Category: citation / citation_author / em_admin
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: De novo designed protein K12


Theoretical massNumber of molelcules
Total (without water)115,7361
Polymers115,7361
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area0 Å2
ΔGint0 kcal/mol
Surface area50420 Å2
MethodPISA

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Components

#1: Protein De novo designed protein K12


Mass: 115735.977 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli (E. coli)
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: De Novo designed Protein K12 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: all / Source: RECOMBINANT
Molecular weightValue: 0.114 MDa / Experimental value: NO
Source (natural)Organism: synthetic construct (others)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4 / Details: Gibco PBS
Buffer componentConc.: 0.4 mg/ml / Name: PBS / Formula: PBS
SpecimenConc.: 3.6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 283 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal magnification: 120000 X / Nominal defocus max: 3740 nm / Nominal defocus min: 100 nm / Cs: 2.7 mm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k)

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Processing

EM softwareName: PHENIX / Version: dev_5240 / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 451357 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT
Atomic model buildingSource name: AlphaFold / Type: in silico model
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 50.43 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00248204
ELECTRON MICROSCOPYf_angle_d0.430211083
ELECTRON MICROSCOPYf_chiral_restr0.03441261
ELECTRON MICROSCOPYf_plane_restr0.00341442
ELECTRON MICROSCOPYf_dihedral_angle_d3.09681123

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