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- EMDB-50040: Scalable protein design using hallucination in a relaxed sequence... -

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Basic information

Entry
Database: EMDB / ID: EMD-50040
TitleScalable protein design using hallucination in a relaxed sequence space
Map dataMain unsharpened map
Sample
  • Organelle or cellular component: De Novo designed Protein K12
    • Protein or peptide: De novo designed protein K12
KeywordsDe novo designed protein K12 / DE NOVO PROTEIN
Biological speciessynthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.36 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 8, 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_50040.png

Downloads & links

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Map

FileDownload / File: emd_50040.map.gz / Format: CCP4 / Size: 36.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMain unsharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.31 Å/pix.
x 212 pix.
= 277.72 Å		1.31 Å/pix.
x 212 pix.
= 277.72 Å		1.31 Å/pix.
x 212 pix.
= 277.72 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.31 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.35445845 - 0.70016897
Average (Standard dev.)0.0003057012 (±0.015795087)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions212212212
Spacing212212212
CellA=B=C: 277.72 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_50040_msk_1.map
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Additional map: Additional, sharpened map used for model building

Fileemd_50040_additional_1.map
AnnotationAdditional, sharpened map used for model building
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Half map: #2

Fileemd_50040_half_map_1.map
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Half map: #1

Fileemd_50040_half_map_2.map
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Sample components

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Entire : De Novo designed Protein K12

EntireName: De Novo designed Protein K12
Components
  • Organelle or cellular component: De Novo designed Protein K12
    • Protein or peptide: De novo designed protein K12

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Supramolecule #1: De Novo designed Protein K12

SupramoleculeName: De Novo designed Protein K12 / type: organelle_or_cellular_component / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 114 KDa

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Macromolecule #1: De novo designed protein K12

MacromoleculeName: De novo designed protein K12 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 115.735977 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MSGAVYFLLL DLRAEVDEEI AWARRLGLDD LVAALEAVRA LIEGALATLE SADFDYLEFT QRLADALSSL VRVYDDLIAR LEEQPATTL RRAYRILLEY RRKEVRELLE AVQELRDVLE TLERLSRRLG RPDFAGWLVS FVLDHYGELV APDILTNPAK G FRALAHLL ...String:
MSGAVYFLLL DLRAEVDEEI AWARRLGLDD LVAALEAVRA LIEGALATLE SADFDYLEFT QRLADALSSL VRVYDDLIAR LEEQPATTL RRAYRILLEY RRKEVRELLE AVQELRDVLE TLERLSRRLG RPDFAGWLVS FVLDHYGELV APDILTNPAK G FRALAHLL RAFLYVLLAL KLRSPDEELR EEARRAVAFL YGEEFVKAHS DEELAELLLE RAREAILEAA RYNSALREEF DA AGGPEGR EAWLERQLLR LRGLVERFLE LWENSELRAG PDGELVAVPG VKGLEIIKKL LEEGKGVNLA LWTLGRLLRA LDL SPEARA AYEAALEALR RARLQLQYVQ SERYEGSDRE RAEAIRAAFE TIRAAAETIR AVIEADTSLP AELKAAYIEV IYAY LLQVA REVRDALWRL AEEILPEYIE KFFKGSEEEQ RLTLYELLRA LGEDYFFLDL EKEGYSEEEL RELFRNAKLE VINAD ESGK IKLYNLILDA KKLNRKVLIK ITLTELSEGS YIITIEVFKS PDAEIPEYEI RVAAVGATSE EILKYLEELK EKAKEG ELI RELLLLYVDR QIAELEEKVA NADKIDPVVA RLAIEEARAR GEELTEADVI EGTRAGYQAA LDVLRRIKAE LEKEKSP EN PFYQFYDKLT EKLKEKGFVS EEEAFEIARE TFGFPADLPP LAAAALRDFA STVLTILEIF KTAEDFSKWY KENKEKLI E LAGLSEEELD KIVRKTLTLL LEALARSVFG SKLGRELLNE ALGTFIKELL ESFFRTHYGL TRGDAVIDFD AKTGILSLR FTPRAYARIR VKEYRDPSLG EKFDNLLDVL SSNPSLKGQV DRLRVSYAFG TPVGTTPALR DATAEDLETD PRLKRHRDFI EEVENLYAE LLIRLEEALK DEPETVEILT EIIGRHLKEV IHDPDVINAL LDRRDLSPEE FAARARAVLD EIIAEEKKLQ E KLLEAVED NPEAKKIVEE IFPKIIATIE RYREWPEREL AGLPLGGSHH HHHH

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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

Concentration3.6 mg/mL
BufferpH: 7.4 / Component - Concentration: 0.4 mg/ml / Component - Formula: PBS / Component - Name: 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) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 3.74 µm / Nominal defocus min: 0.1 µm / Nominal magnification: 120000
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: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 451357
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
RefinementProtocol: FLEXIBLE FIT
Output model

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

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