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- EMDB-50113: Scalable protein design using hallucination in a relaxed sequence... -

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Basic information

Entry
Database: EMDB / ID: EMD-50113
TitleScalable protein design using hallucination in a relaxed sequence space
Map dataPrimary, unsharpened map
Sample
  • Organelle or cellular component: De novo designed protein K10
    • Protein or peptide: De novo designed Protein K10
KeywordsDe novo designed protein K12 / DE NOVO PROTEIN
Biological speciessynthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsFrank CJ / Dietz H
Funding supportEuropean Union, Germany, 2 items
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 17, 2024-
Header (metadata) releaseOct 16, 2024-
Map releaseOct 16, 2024-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_50113.png

Downloads & links

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Map

FileDownload / File: emd_50113.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationPrimary, unsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.14 Å/pix.
x 256 pix.
= 291.84 Å		1.14 Å/pix.
x 256 pix.
= 291.84 Å		1.14 Å/pix.
x 256 pix.
= 291.84 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.14 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.3235329 - 0.7452594
Average (Standard dev.)-0.0014398412 (±0.011911914)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 291.84 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50113_msk_1.map
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Additional map: Additional Sharpened Map used for model building

Fileemd_50113_additional_1.map
AnnotationAdditional Sharpened Map used for model building
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Half map: Half map A

Fileemd_50113_half_map_1.map
AnnotationHalf map A
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Half map: Half Map B

Fileemd_50113_half_map_2.map
AnnotationHalf Map B
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Sample components

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Entire : De novo designed protein K10

EntireName: De novo designed protein K10
Components
  • Organelle or cellular component: De novo designed protein K10
    • Protein or peptide: De novo designed Protein K10

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Supramolecule #1: De novo designed protein K10

SupramoleculeName: De novo designed protein K10 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 106.095 KDa

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Macromolecule #1: De novo designed Protein K10

MacromoleculeName: De novo designed Protein K10 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 106.221523 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: VFAPRKTFES REAAEKWFEQ WLRDNGLLAP EGAESLPVTV YATYKIAGDP NVHVERHEVD APATLPRDEA GNPARTLEEF RAFLARRTA AEGVSPAQQE VDLARHLAWL AETEGEEAAT AFVRSLLPPD APTRPGEPAL GELFDPLDPA AVAVAHEAFA R FYAGFRRR ...String:
VFAPRKTFES REAAEKWFEQ WLRDNGLLAP EGAESLPVTV YATYKIAGDP NVHVERHEVD APATLPRDEA GNPARTLEEF RAFLARRTA AEGVSPAQQE VDLARHLAWL AETEGEEAAT AFVRSLLPPD APTRPGEPAL GELFDPLDPA AVAVAHEAFA R FYAGFRRR FLPALEEARA GRRPSGLPEW LAEHYTAEDF ELVREQVERV AALVERLAEL LAAGAPEEEV RAVLAELAAL LR EPEAVRA LVLAFYAFPD LLSPADFKAI LGFLASVVAQ VEVAALTPAQ RAEVLRRFDL SEAEEEEALR LYGQELAARW LAS LLYALL REVPDIPYLA QLLARAVLES AELLLESGEP RLAVRYLTQA LYALVHRNYL ALKLVAIEAV LEALRSAIER AEEL LEKYK ETGDEGAKVK ALELILRVID LLTSESTAVV FSFATLEQQR EFLLNLFRLQ KLLGDKLIVA IVVTRRSNPE VREFF REFV IDAIKEYFED KEVAEAIIKY LEEARAGGPA KGLAAYLFEH LSSIELLLTF LDTAKEHYEK QKAAGEPVDF SDLPKL FFE KFGEELVKRI EALIETLEEL LRNGLLPAEQ RPRVRAFVEG LRVLRRFLER LIELEKIKSE LSEEEYKKKL EEIFEEV EA EADPENPFEL AFFSLIRILL DEGGPGSPVY EEALARLERA VELDPALRFV VETTLRFIDW ARAQGLSKEE TLLLLIHA F TNAALVAALL DAETLAAALS SDPAAIPLVL PRNPNVAKFI KRVGDDTIIV VVLFGLRTPA GLREFYDLRI AYLEKTVAD LTARADRVLT DPSVPGSPAE REARAAGLRA RAREAQLQLE LTRLLRRLRV ENATLSRNQW LAAVARESLA WLEENGFETV EALLATEAG RALLRELARL LGEFADDPAA VEAARLAEEV LYLGDPEAFA RLRELLAELA ARFAAQPPVP R

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3.8 mg/mL
BufferpH: 7.4 / Component - Concentration: 1.0 x / Component - Formula: PBS / Component - Name: Gibco PBS / Details: Gibco PBS
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 283 K

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 3 / Average electron dose: 18.93 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionNumber classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 540298
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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