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- PDB-8s89: Efficient and scalable protein design using a relaxed sequence space -

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Entry
Database: PDB / ID: 8s89
TitleEfficient and scalable protein design using a relaxed sequence space
ComponentsDE NOVO PROTEIN P400
KeywordsDE NOVO PROTEIN / P400
Biological speciessynthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 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
DepositionMar 6, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 16, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 6, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: DE NOVO PROTEIN P400
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,7293
Polymers43,5371
Non-polymers1922
Water3,171176
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint-15 kcal/mol
Surface area18380 Å2
Unit cell
Length a, b, c (Å)43.596, 62.591, 80.269
Angle α, β, γ (deg.)90.000, 97.354, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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Components

#1: Protein DE NOVO PROTEIN P400


Mass: 43536.793 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)
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 176 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.49 Å3/Da / Density % sol: 50.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 0.2 mmol magnesium sulfate, 28-32% PEG4000, 0.1 M TRIS pH 8.5-9.3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL02U1 / Wavelength: 0.9791 Å
DetectorType: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Oct 1, 2023
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9791 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 25154 / % possible obs: 99.92 % / Redundancy: 6.1 % / Biso Wilson estimate: 28.25 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.1026 / Rpim(I) all: 0.04557 / Net I/σ(I): 11.66
Reflection shellResolution: 2.1→2.18 Å / Redundancy: 5.8 % / Rmerge(I) obs: 0.6793 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 2518 / CC1/2: 0.81 / Rpim(I) all: 0.3076 / % possible all: 99.84

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Processing

Software
NameVersionClassification
PHENIX1.18.1_3865refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.1→43.24 Å / SU ML: 0.2055 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.0602
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2426 1303 5.18 %
Rwork0.2063 23851 -
obs0.2082 25154 99.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 33.32 Å2
Refinement stepCycle: LAST / Resolution: 2.1→43.24 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3055 0 10 176 3241
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.013103
X-RAY DIFFRACTIONf_angle_d1.20714213
X-RAY DIFFRACTIONf_chiral_restr0.0585514
X-RAY DIFFRACTIONf_plane_restr0.0062542
X-RAY DIFFRACTIONf_dihedral_angle_d25.67711136
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.180.28641570.26752621X-RAY DIFFRACTION99.86
2.18-2.280.28831230.22972647X-RAY DIFFRACTION100
2.28-2.40.25681390.21892638X-RAY DIFFRACTION100
2.4-2.550.29641410.2242650X-RAY DIFFRACTION100
2.55-2.750.29181450.22532644X-RAY DIFFRACTION100
2.75-3.030.29351470.23612618X-RAY DIFFRACTION99.96
3.03-3.470.27781380.21932681X-RAY DIFFRACTION100
3.47-4.370.22761430.17932666X-RAY DIFFRACTION100
4.37-43.240.17311700.17492686X-RAY DIFFRACTION99.51

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