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中国生物工程杂志

China Biotechnology
China Biotechnology
China Biotechnology  2023, Vol. 43 Issue (7): 60-76    DOI: 10.13523/j.cb.2212025
    
Application of Computational Simulation in Protein Assembly
Ding-yuan LU1,Qi-bin WANG1,Hu LIU1,**(),Chun LI1,2,**()
1 School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488, China
2 Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
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Abstract  

Protein assembly technology has developed rapidly and is widely used in biocatalysis, biosensors, and drug release. It has become an important part of bioengineering. Due to the complexity of protein-protein interactions and insufficient understanding of protein folding and molecular recognition, designing complex protein assemblies is very challenging. With the continuous development of computer technology and molecular simulation, researchers have gradually realized the precise design of protein assemblies with atomic-and molecular-level accuracy, predicted the structure of protein assemblies, and further designed catalytic sites on protein assemblies to obtain a.pngicial biocatalysis of assembled enzymes. In recent years, a.pngicial intelligence technologies such as machine learning have also been applied to protein assembly design, contributing to the development of protein assembly research. Here, the research progress of computational simulation technology in design of protein assembly, prediction of assembly structure, and catalytic site design and its application in new enzyme design, drug release, biosensor and other areas are reviewed, in order to guide the design and optimization of protein assembly for more different application fields through basic theoretical research.

Key words： Computational simulation      Protein assembly      Prediction of assembly structure      Catalytic site design     
Received: 18 December 2022      Published: 03 August 2023
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Ding-yuan LU
Qi-bin WANG
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Chun LI
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Ding-yuan LU, Qi-bin WANG, Hu LIU, Chun LI. Application of Computational Simulation in Protein Assembly. China Biotechnology, 2023, 43(7): 60-76.

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https://manu60.magtech.com.cn/biotech/10.13523/j.cb.2212025     OR     https://manu60.magtech.com.cn/biotech/Y2023/V43/I7/60

Fig.1 Application of computational simulation in natural protein module assembly (a) Two-component assembly of 120 subunits [5] (b) Schematic diagram of protein nanostructures formed by Ni2+ -His coordination[10] (c) Trimer esterase used in the design (the C-terminus of which is represented by a red sphere) and the structure of a tetrameric coiled coil[9]
De novo building blocks Principles or algorithms Assembly properties References
Homotetrameric bundle Thiol-maleimide“click”reaction 1D, high stability, controllable size and spatial display [16]
Single chain homodimeric bundle Rosetta HBNet algorithm Pseudosymmetric 2D assemblies based on a C12 symmetric layer group [17]
Helical hairpin monomer Rosetta Homo-oligomers with central hydrogen-bond networks [14]
De novo repeat protein Rosetta Homotrimeric metalloprotein with a trisbipyridyl core [18]
De novo repeat protein CoCoPOD Zn2+-dependent CCPO cages [19]
α-Helical repeat protein Rosetta Homo-oligomeric protein complexes with cyclic symmetry [15]
WA20-foldon fusion protein Coot modelling Highly symmetric hexamer, dodecamer and octadecamer [20]
Homotrimeric parallel coiled-coil Probabilistic protein design 3D, macroscopic protein crystals [21]
Heterodimeric and homotrimeric coiled-coil bundles MD simulation Hexagonal networks, cage-like particles [22]
“Sticky ended”dimeric coiled coil MD simulation MAKECCSC modelling 1D gigadalton.pngf peptide fibers [23]
De novo α-helics CCBuilder Water-soluble parallel α-helical barrels [24]
De novo αβ-proteins Rosetta C2~C5 cyclic oligomer [25]
De novo βαβ fold Rosetta Novel topology, self-assemble into a fibril [26]
De novo αβ-proteins ProteinMPNN C3~C33 cyclic oligomer [27]
Table 1 Applications of computational method in designing de novo building block and its assembly
Fig.2 Application of computational simulation in de novo protein module assembly (a) The homologous dimers designed from scratch are connected into a single chain and symmetrically assembled in the C12 layer group with three parameters a, b and θ[17] (b) The unnatural amino acid bipyridine-alanine (Bpy-Ala) and Fe2+ are assembled by metal coordination[18] (c) Schematic representation of the assembly of the WA20-foldon fusion protein[20] (d) The alpha-β-proteins designed from scratch were bused into a ring assembly conformation[25]
Fig.3 Application of computational simulation in predicting protein assembly based on structural information (a) SIKE dimer model predicted by ZDOCK and ClusPro[57] (b) Schematic diagram of wheel deployment[22] (c) Curvature observed after 5 ns MD simulation[22]
Scaffolds Assembly
strategies		 Active
centers		 Locations Catalytic
functions		 References
Heptameric α-
helical barrel		 Hydrophobic interaction Cys-His-Glu triads Lumen of α-helical barrel p-Nitrophenyl acetate hydrolysis [63]
TMV coat protein
nanodisks or nanotubes		 Natural protein
aggregation		 Selenocysteine Outer surface of nanodisks and nanotubes Catalyze the reduction of H2O2 by glutathione [64]
LmrR dimer Cysteine conjugation Cu2+ Hydrophobic pore of dimer center Catalyze Diels-Alder reaction [65]
Heterotetrameric helical bundle Noncovalent interaction Diiron(II/III) ions Cavity of helical bundle Oxidation of 4-aminophenol [66]
Cytochrome cb562
tetramer		 Metal coordination,
disulfide bond		 Zn2+, His, Glu Interface of monomers Ampicillin hydrolysis [67]
MID1-zinc homodimer Metal coordination Zn2+, His, tartrate A cleft of dimer interface Hydrolysis of 4-nitrophenyl acetate and 4-nitrophenyl phosphate [68]
Homotetrameric coiled coils Noncovalent interaction Cu2+, His Lumen of coiled coils Reduction of nitrite [69]
Parallel coiled-
coil homotetramers		 Noncovalent interaction Cys, Lys, His Interface between
helical subunits		 Intermodular aminoacyl transfer [70]
Heterodimeric coiled-coil Electrostatic Cys Interface of heterodimer Ligate two short peptide
fragments		 [71]
Table 2 Introduction of catalytically active site in protein assembly
Fig.4 Application of computational simulation in designing specific modified catalytic sites (a) GPx mimics Se-TMVcp142Cys149Arg assembled into an a.pngicial nanozyme[64] (b) De novo C45 protein calculation model and the peroxidase catalyzed reaction[72]
Fig.5 Application of computational simulation in designing catalytic sites of different metal ions (a) The CuII complex is attached to the dimer interface of the protein scaffold, and the ligand is attached to the dimer interface[65] (b) Subunit composition of DFtetA2B2 and DFtet AaAbB2[66] (c) The crystal structure of Zn8: AB34[67]
Fig.6 Application of computational simulation in studying the catalytic mechanism of assembled enzyme (a) A nick (red grid) on the MID1-Zn interface and an open zinc coordination sites[68] (b) Model of 4AP bound to DFtet A2B2. The carbons of thephenol are in cyan[66] (c) DhaA115 dimer interface design[77]
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