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Hierarchical design of artificial proteins and complexes toward synthetic structural biology

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Abstract

In multiscale structural biology, synthetic approaches are important to demonstrate biophysical principles and mechanisms underlying the structure, function, and action of bio-nanomachines. A central goal of “synthetic structural biology” is the design and construction of artificial proteins and protein complexes as desired. In this paper, I review recent remarkable progress of an array of approaches for hierarchical design of artificial proteins and complexes that signpost the path forward toward synthetic structural biology as an emerging interdisciplinary field. Topics covered include combinatorial and protein-engineering approaches for directed evolution of artificial binding proteins and membrane proteins, binary code strategy for structural and functional de novo proteins, protein nanobuilding block strategy for constructing nano-architectures, protein–metal–organic frameworks for 3D protein complex crystals, and rational and computational approaches for design/creation of artificial proteins and complexes, novel protein folds, ideal/optimized protein structures, novel binding proteins for targeted therapeutics, and self-assembling nanomaterials. Protein designers and engineers look toward a bright future in synthetic structural biology for the next generation of biophysics and biotechnology.

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References

  • Abe S, Ueno T (2015) Design of protein crystals in the development of solid biomaterials. RSC Adv 5:21366–21375

    Article  CAS  Google Scholar 

  • Abe S, Maity B, Ueno T (2016) Design of a confined environment using protein cages and crystals for the development of biohybrid materials. Chem Commun 52:6496–6512

    Article  CAS  Google Scholar 

  • Ahnert SE, Marsh JA, Hernandez H, Robinson CV, Teichmann SA (2015) Principles of assembly reveal a periodic table of protein complexes. Science 350:aaa2245

    Article  PubMed  CAS  Google Scholar 

  • Anfinsen CB (1973) Principles that govern the folding of protein chains. Science 181:223–230

    Article  CAS  PubMed  Google Scholar 

  • Arai R, Kobayashi N, Kimura A, Sato T, Matsuo K, Wang AF, Platt JM, Bradley LH, Hecht MH (2012) Domain-swapped dimeric structure of a stable and functional de novo four-helix bundle protein, WA20. J Phys Chem B 116:6789–6797

    Article  CAS  PubMed  Google Scholar 

  • Arisaka F, Yap ML, Kanamaru S, Rossmann MG (2016) Molecular assembly and structure of the bacteriophage T4 tail. Biophys Rev 8:385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JB, Subramanian RH, Churchfield LA, Tezcan FA (2016) Metal-directed Design of Supramolecular Protein Assemblies. Methods Enzymol 580:223–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JB, Zhang L, Chiong JA, Ahn S, Tezcan FA (2017) Synthetic modularity of protein-metal-organic frameworks. J Am Chem Soc 139:8160–8166

    Article  CAS  PubMed  Google Scholar 

  • Baker D (2010) An exciting but challenging road ahead for computational enzyme design. Protein Sci 19:1817–1819

  • Baker D (2014) Protein folding, structure prediction and design. Biochem Soc Trans 42:225–229

  • Bale JB, Gonen S, Liu Y, Sheffler W, Ellis D, Thomas C, Cascio D, Yeates TO, Gonen T, King NP, Baker D (2016) Accurate design of megadalton-scale two-component icosahedral protein complexes. Science 353:389–394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bender BJ, Cisneros A 3rd, Duran AM, Finn JA, Fu D, Lokits AD, Mueller BK, Sangha AK, Sauer MF, Sevy AM, Sliwoski G, Sheehan JH, DiMaio F, Meiler J, Moretti R (2016) Protocols for molecular Modeling with Rosetta3 and RosettaScripts. Biochemistry 55:4748–4763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bessette PH, Rice JJ, Daugherty PS (2004) Rapid isolation of high-affinity protein binding peptides using bacterial display. Protein Eng Des Sel 17:731–739

    Article  CAS  PubMed  Google Scholar 

  • Bick MJ, Greisen PJ, Morey KJ, Antunes MS, La D, Sankaran B, Reymond L, Johnsson K, Medford JI, Baker D (2017) Computational design of environmental sensors for the potent opioid fentanyl. elife 6:e28909

    Article  PubMed  PubMed Central  Google Scholar 

  • Boder ET, Wittrup KD (1997) Yeast surface display for screening combinatorial polypeptide libraries. Nat Biotechnol 15:553–557

    Article  CAS  PubMed  Google Scholar 

  • Boersma YL, Pluckthun A (2011) DARPins and other repeat protein scaffolds: advances in engineering and applications. Curr Opin Biotechnol 22:849–857

    Article  CAS  PubMed  Google Scholar 

  • Boucher JI, Bolon DN, Tawfik DS (2016) Quantifying and understanding the fitness effects of protein mutations: laboratory versus nature. Protein Sci 25:1219–1226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bowers PM, Strauss CE, Baker D (2000) De novo protein structure determination using sparse NMR data. J Biomol NMR 18:311–318

    Article  CAS  PubMed  Google Scholar 

  • Boyken SE, Chen Z, Groves B, Langan RA, Oberdorfer G, Ford A, Gilmore JM, Xu C, DiMaio F, Pereira JH, Sankaran B, Seelig G, Zwart PH, Baker D (2016) De novo design of protein homo-oligomers with modular hydrogen-bond network-mediated specificity. Science 352:680–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradley LH, Kleiner RE, Wang AF, Hecht MH, Wood DW (2005) An intein-based genetic selection allows the construction of a high-quality library of binary patterned de novo protein sequences. Protein Eng Des Sel 18:201–207

    Article  CAS  PubMed  Google Scholar 

  • Brodin JD, Ambroggio XI, Tang C, Parent KN, Baker TS, Tezcan FA (2012) Metal-directed, chemically tunable assembly of one-, two- and three-dimensional crystalline protein arrays. Nat Chem 4:375–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Brodin JD, Smith SJ, Carr JR, Tezcan FA (2015) Designed, helical protein Nanotubes with variable diameters from a single building block. J Am Chem Soc 137:10468–10471

    Article  CAS  PubMed  Google Scholar 

  • Brunette TJ, Parmeggiani F, Huang PS, Bhabha G, Ekiert DC, Tsutakawa SE, Hura GL, Tainer JA, Baker D (2015) Exploring the repeat protein universe through computational protein design. Nature 528:580–584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryson JW, Betz SF, Lu HS, Suich DJ, Zhou HX, O'Neil KT, DeGrado WF (1995) Protein design: a hierarchic approach. Science 270:935–941

    Article  CAS  PubMed  Google Scholar 

  • Burgess NC, Sharp TH, Thomas F, Wood CW, Thomson AR, Zaccai NR, Brady RL, Serpell LC, Woolfson DN (2015) Modular Design of Self-Assembling Peptide-Based Nanotubes. J Am Chem Soc 137:10554–10562

    Article  CAS  PubMed  Google Scholar 

  • Burton AJ, Thomson AR, Dawson WM, Brady RL, Woolfson DN (2016) Installing hydrolytic activity into a completely de novo protein framework. Nat Chem 8:837–844

    Article  CAS  PubMed  Google Scholar 

  • Cherny I, Korolev M, Koehler AN, Hecht MH (2012) Proteins from an unevolved library of de novo designed sequences bind a range of small molecules. ACS Synth Biol 1:130–138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chevalier A, Silva DA, Rocklin GJ, Hicks DR, Vergara R, Murapa P, Bernard SM, Zhang L, Lam KH, Yao G, Bahl CD, Miyashita SI, Goreshnik I, Fuller JT, Koday MT, Jenkins CM, Colvin T, Carter L, Bohn A, Bryan CM, Fernandez-Velasco DA, Stewart L, Dong M, Huang X, Jin R, Wilson IA, Fuller DH, Baker D (2017) Massively parallel de novo protein design for targeted therapeutics. Nature 550:74–79

    CAS  PubMed  PubMed Central  Google Scholar 

  • Churchfield LA, Medina-Morales A, Brodin JD, Perez A, Tezcan FA (2016) De novo design of an allosteric metalloprotein assembly with strained disulfide bonds. J Am Chem Soc 138:13163–13166

  • Crick FHC (1953a) The Fourier transform of a coiled-coil. Acta Crystallogr 6:685–689

    Article  CAS  Google Scholar 

  • Crick FHC (1953b) The packing of α-helices: simple coiled-coils. Acta Crystallogr 6:689–697

    Article  CAS  Google Scholar 

  • Dahiyat BI, Mayo SL (1997) De novo protein design: fully automated sequence selection. Science 278:82–87

    Article  CAS  PubMed  Google Scholar 

  • Das R, Baker D (2008) Macromolecular modeling with rosetta. Annu Rev Biochem 77:363–382

    Article  CAS  PubMed  Google Scholar 

  • de Bono S, Riechmann L, Girard E, Williams RL, Winter G (2005) A segment of cold shock protein directs the folding of a combinatorial protein. Proc Natl Acad Sci U S A 102:1396–1401

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Digianantonio KM, Hecht MH (2016) A protein constructed de novo enables cell growth by altering gene regulation. Proc Natl Acad Sci U S A 113:2400–2405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Digianantonio KM, Korolev M, Hecht MH (2017) A non-natural protein rescues cells deleted for a key enzyme in central metabolism. ACS Synth Biol 6:694–700

    Article  CAS  PubMed  Google Scholar 

  • DiMaio F, Leaver-Fay A, Bradley P, Baker D, Andre I (2011) Modeling symmetric macromolecular structures in Rosetta3. PLoS ONE 6:e20450

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle L, Hallinan J, Bolduc J, Parmeggiani F, Baker D, Stoddard BL, Bradley P (2015) Rational design of alpha-helical tandem repeat proteins with closed architectures. Nature 528:585–588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fallas JA, Ueda G, Sheffler W, Nguyen V, McNamara DE, Sankaran B, Pereira JH, Parmeggiani F, Brunette TJ, Cascio D, Yeates TR, Zwart P, Baker D (2017) Computational design of self-assembling cyclic protein homo-oligomers. Nat Chem 9:353–360

    Article  CAS  PubMed  Google Scholar 

  • Fisher MA, McKinley KL, Bradley LH, Viola SR, Hecht MH (2011) De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth. PLoS ONE 6:e15364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fleishman SJ, Whitehead TA, Ekiert DC, Dreyfus C, Corn JE, Strauch EM, Wilson IA, Baker D (2011) Computational design of proteins targeting the conserved stem region of influenza hemagglutinin. Science 332:816–821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fletcher JM, Harniman RL, Barnes FR, Boyle AL, Collins A, Mantell J, Sharp TH, Antognozzi M, Booth PJ, Linden N, Miles MJ, Sessions RB, Verkade P, Woolfson DN (2013) Self-assembling cages from coiled-coil peptide modules. Science 340:595–599

    Article  CAS  PubMed  Google Scholar 

  • Forsyth CM, Juan V, Akamatsu Y, DuBridge RB, Doan M, Ivanov AV, Ma Z, Polakoff D, Razo J, Wilson K, Powers DB (2013) Deep mutational scanning of an antibody against epidermal growth factor receptor using mammalian cell display and massively parallel pyrosequencing. MAbs 5:523–532

    Article  PubMed  PubMed Central  Google Scholar 

  • Fowler DM, Fields S (2014) Deep mutational scanning: a new style of protein science. Nat Methods 11:801–807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fowler DM, Araya CL, Fleishman SJ, Kellogg EH, Stephany JJ, Baker D, Fields S (2010) High-resolution mapping of protein sequence-function relationships. Nat Methods 7:741–746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii S, Matsuura T, Sunami T, Kazuta Y, Yomo T (2013) In vitro evolution of alpha-hemolysin using a liposome display. Proc Natl Acad Sci U S A 110:16796–16801

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fujii S, Matsuura T, Sunami T, Nishikawa T, Kazuta Y, Yomo T (2014) Liposome display for in vitro selection and evolution of membrane proteins. Nat Protoc 9:1578–1591

    Article  CAS  PubMed  Google Scholar 

  • Fujino Y, Fujita R, Wada K, Fujishige K, Kanamori T, Hunt L, Shimizu Y, Ueda T (2012) Robust in vitro affinity maturation strategy based on interface-focused high-throughput mutational scanning. Biochem Biophys Res Commun 428:395–400

    Article  CAS  PubMed  Google Scholar 

  • Fujiwara D, Kitada H, Oguri M, Nishihara T, Michigami M, Shiraishi K, Yuba E, Nakase I, Im H, Cho S, Joung JY, Kodama S, Kono K, Ham S, Fujii I (2016) A cyclized helix-loop-helix peptide as a molecular scaffold for the design of inhibitors of intracellular protein-protein interactions by epitope and arginine grafting. Angew Chem Int Ed 55:10612–10615

  • Giger L, Caner S, Obexer R, Kast P, Baker D, Ban N, Hilvert D (2013) Evolution of a designed retro-aldolase leads to complete active site remodeling. Nat Chem Biol 9:494–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilbreth RN, Koide S (2012) Structural insights for engineering binding proteins based on non-antibody scaffolds. Curr Opin Struct Biol 22:413–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Go A, Kim S, Baum J, Hecht MH (2008) Structure and dynamics of de novo proteins from a designed superfamily of 4-helix bundles. Protein Sci 17:821–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonen S, DiMaio F, Gonen T, Baker D (2015) Design of ordered two-dimensional arrays mediated by noncovalent protein-protein interfaces. Science 348:1365–1368

    Article  CAS  PubMed  Google Scholar 

  • Goto Y, Katoh T, Suga H (2011) Flexizymes for genetic code reprogramming. Nat Protoc 6:779–790

    Article  CAS  PubMed  Google Scholar 

  • Gradisar H, Bozic S, Doles T, Vengust D, Hafner-Bratkovic I, Mertelj A, Webb B, Sali A, Klavzar S, Jerala R (2013) Design of a single-chain polypeptide tetrahedron assembled from coiled-coil segments. Nat Chem Biol 9:362–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Graziano JJ, Liu W, Perera R, Geierstanger BH, Lesley SA, Schultz PG (2008) Selecting folded proteins from a library of secondary structural elements. J Am Chem Soc 130:176–185

    Article  CAS  PubMed  Google Scholar 

  • Grigoryan G, Degrado WF (2011) Probing designability via a generalized model of helical bundle geometry. J Mol Biol 405:1079–1100

    Article  CAS  PubMed  Google Scholar 

  • Grigoryan G, Kim YH, Acharya R, Axelrod K, Jain RM, Willis L, Drndic M, Kikkawa JM, DeGrado WF (2011) Computational design of virus-like protein assemblies on carbon nanotube surfaces. Science 332:1071–1076

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gully BS, Shah KR, Lee M, Shearston K, Smith NM, Sadowska A, Blythe AJ, Bernath-Levin K, Stanley WA, Small ID, Bond CS (2015) The design and structural characterization of a synthetic pentatricopeptide repeat protein. Acta Crystallogr D 71:196–208

    Article  CAS  PubMed  Google Scholar 

  • Guthe S, Kapinos L, Moglich A, Meier S, Grzesiek S, Kiefhaber T (2004) Very fast folding and association of a trimerization domain from bacteriophage T4 fibritin. J Mol Biol 337:905–915

    Article  PubMed  CAS  Google Scholar 

  • Hanes J, Pluckthun A (1997) In vitro selection and evolution of functional proteins by using ribosome display. Proc Natl Acad Sci U S A 94:4937–4942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harbury PB, Plecs JJ, Tidor B, Alber T, Kim PS (1998) High-resolution protein design with backbone freedom. Science 282:1462–1467

    Article  CAS  PubMed  Google Scholar 

  • Hecht MH, Das A, Go A, Bradley LH, Wei Y (2004) De novo proteins from designed combinatorial libraries. Protein Sci 13:1711–1723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hietpas RT, Jensen JD, Bolon DNA (2011) Experimental illumination of a fitness landscape. Proc Natl Acad Sci U S A 108:7896–7901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hipolito CJ, Suga H (2012) Ribosomal production and in vitro selection of natural product-like peptidomimetics: the FIT and RaPID systems. Curr Opin Chem Biol 16:196–203

    Article  CAS  PubMed  Google Scholar 

  • Hirota S, Hattori Y, Nagao S, Taketa M, Komori H, Kamikubo H, Wang Z, Takahashi I, Negi S, Sugiura Y, Kataoka M, Higuchi Y (2010) Cytochrome c polymerization by successive domain swapping at the C-terminal helix. Proc Natl Acad Sci U S A 107:12854–12859

  • Hoegler KJ, Hecht MH (2016) A de novo protein confers copper resistance in Escherichia Coli. Protein Sci 25:1249–1259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Honda S, Yamasaki K, Sawada Y, Morii H (2004) 10 residue folded peptide designed by segment statistics. Structure 12:1507–1518

    Article  CAS  PubMed  Google Scholar 

  • Honda S, Akiba T, Kato YS, Sawada Y, Sekijima M, Ishimura M, Ooishi A, Watanabe H, Odahara T, Harata K (2008) Crystal structure of a ten-amino acid protein. J Am Chem Soc 130:15327–15331

    Article  CAS  PubMed  Google Scholar 

  • Hoogenboom HR (2005) Selecting and screening recombinant antibody libraries. Nat Biotechnol 23:1105–1116

    Article  CAS  PubMed  Google Scholar 

  • Hsia Y, Bale JB, Gonen S, Shi D, Sheffler W, Fong KK, Nattermann U, Xu C, Huang PS, Ravichandran R, Yi S, Davis TN, Gonen T, King NP, Baker D (2016) Design of a hyperstable 60-subunit protein icosahedron. Nature 535:136–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang PS, Oberdorfer G, Xu C, Pei XY, Nannenga BL, Rogers JM, DiMaio F, Gonen T, Luisi B, Baker D (2014) High thermodynamic stability of parametrically designed helical bundles. Science 346:481–485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang PS, Boyken SE, Baker D (2016) The coming of age of de novo protein design. Nature 537:320–327

    Article  CAS  PubMed  Google Scholar 

  • Jardine JG, Kulp DW, Havenar-Daughton C, Sarkar A, Briney B, Sok D, Sesterhenn F, Ereno-Orbea J, Kalyuzhniy O, Deresa I, Hu X, Spencer S, Jones M, Georgeson E, Adachi Y, Kubitz M, deCamp AC, Julien JP, Wilson IA, Burton DR, Crotty S, Schief WR (2016) HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen. Science 351:1458–1463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang L, Althoff EA, Clemente FR, Doyle L, Rothlisberger D, Zanghellini A, Gallaher JL, Betker JL, Tanaka F, Barbas CF 3rd, Hilvert D, Houk KN, Stoddard BL, Baker D (2008) De novo computational design of retro-aldol enzymes. Science 319:1387–1391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Joh NH, Wang T, Bhate MP, Acharya R, Wu Y, Grabe M, Hong M, Grigoryan G, DeGrado WF (2014) De novo design of a transmembrane Zn2+-transporting four-helix bundle. Science 346:1520–1524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jost C, Pluckthun A (2014) Engineered proteins with desired specificity: DARPins, other alternative scaffolds and bispecific IgGs. Curr Opin Struct Biol 27:102–112

    Article  CAS  PubMed  Google Scholar 

  • Jumawid MT, Takahashi T, Yamazaki T, Ashigai H, Mihara H (2009) Selection and structural analysis of de novo proteins from an α3β3 genetic library. Protein Sci 18:384–398

  • Kamtekar S, Schiffer JM, Xiong H, Babik JM, Hecht MH (1993) Protein design by binary patterning of polar and nonpolar amino acids. Science 262:1680–1685

    Article  CAS  PubMed  Google Scholar 

  • Kaufmann KW, Lemmon GH, Deluca SL, Sheehan JH, Meiler J (2010) Practically useful: what the Rosetta protein modeling suite can do for you. Biochemistry 49:2987–2998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ke Y (2014) Designer three-dimensional DNA architectures. Curr Opin Struct Biol 27:122–128

    Article  CAS  PubMed  Google Scholar 

  • Keefe AD, Szostak JW (2001) Functional proteins from a random-sequence library. Nature 410:715–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim KH, Ko DK, Kim YT, Kim NH, Paul J, Zhang SQ, Murray CB, Acharya R, DeGrado WF, Kim YH, Grigoryan G (2016) Protein-directed self-assembly of a fullerene crystal. Nat Commun 7:11429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King NP, Sheffler W, Sawaya MR, Vollmar BS, Sumida JP, Andre I, Gonen T, Yeates TO, Baker D (2012) Computational design of self-assembling protein nanomaterials with atomic level accuracy. Science 336:1171–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • King NP, Bale JB, Sheffler W, McNamara DE, Gonen S, Gonen T, Yeates TO, Baker D (2014) Accurate design of co-assembling multi-component protein nanomaterials. Nature 510:103–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kiss G, Celebi-Olcum N, Moretti R, Baker D, Houk KN (2013) Computational enzyme design. Angew Chem Int Ed 52:5700–5725

    Article  CAS  Google Scholar 

  • Kobayashi N, Arai R (2017) Design and construction of self-assembling supramolecular protein complexes using artificial and fusion proteins as nanoscale building blocks. Curr Opin Biotech 46:57–65

    Article  CAS  PubMed  Google Scholar 

  • Kobayashi N, Yanase K, Sato T, Unzai S, Hecht MH, Arai R (2015) Self-assembling Nano-architectures created from a protein Nano-building block using an Intermolecularly folded Dimeric de novo protein. J Am Chem Soc 137:11285–11293

    Article  CAS  PubMed  Google Scholar 

  • Koenig P, Lee CV, Sanowar S, Wu P, Stinson J, Harris SF, Fuh G (2015) Deep sequencing-guided Design of a High Affinity Dual Specificity Antibody to target two Angiogenic factors in Neovascular age-related macular degeneration. J Biol Chem 290:21773–21786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koga N, Tatsumi-Koga R, Liu G, Xiao R, Acton TB, Montelione GT, Baker D (2012) Principles for designing ideal protein structures. Nature 491:222–227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kries H, Blomberg R, Hilvert D (2013) De novo enzymes by computational design. Curr Opin Chem Biol 17:221–228

    Article  CAS  PubMed  Google Scholar 

  • Kuhlman B, Dantas G, Ireton GC, Varani G, Stoddard BL, Baker D (2003) Design of a novel globular protein fold with atomic-level accuracy. Science 302:1364–1368

    Article  CAS  PubMed  Google Scholar 

  • Lai YT, Cascio D, Yeates TO (2012) Structure of a 16-nm cage designed by using protein oligomers. Science 336:1129

    Article  CAS  PubMed  Google Scholar 

  • Lai YT, Reading E, Hura GL, Tsai KL, Laganowsky A, Asturias FJ, Tainer JA, Robinson CV, Yeates TO (2014) Structure of a designed protein cage that self-assembles into a highly porous cube. Nat Chem 6:1065–1071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leaver-Fay A, Tyka M, Lewis SM, Lange OF, Thompson J, Jacak R, Kaufman K, Renfrew PD, Smith CA, Sheffler W, Davis IW, Cooper S, Treuille A, Mandell DJ, Richter F, Ban YE, Fleishman SJ, Corn JE, Kim DE, Lyskov S, Berrondo M, Mentzer S, Popovic Z, Havranek JJ, Karanicolas J, Das R, Meiler J, Kortemme T, Gray JJ, Kuhlman B, Baker D, Bradley P (2011) ROSETTA3: an object-oriented software suite for the simulation and design of macromolecules. Methods Enzymol 487:545–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee SC, Park K, Han J, Lee JJ, Kim HJ, Hong S, Heu W, Kim YJ, Ha JS, Lee SG, Cheong HK, Jeon YH, Kim D, Kim HS (2012) Design of a binding scaffold based on variable lymphocyte receptors of jawless vertebrates by module engineering. Proc Natl Acad Sci U S A 109:3299–3304

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Leiman PG, Kanamaru S, Mesyanzhinov VV, Arisaka F, Rossmann MG (2003) Structure and morphogenesis of bacteriophage T4. Cell Mol Life Sci 60:2356–2370

    Article  CAS  PubMed  Google Scholar 

  • Lin YR, Koga N, Tatsumi-Koga R, Liu G, Clouser AF, Montelione GT, Baker D (2015a) Control over overall shape and size in de novo designed proteins. Proc Natl Acad Sci U S A 112:E5478–E5485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin YW, Nagao S, Zhang M, Shomura Y, Higuchi Y, Hirota S (2015b) Rational design of heterodimeric protein using domain swapping for myoglobin. Angew Chem Int Ed 54:511–515

    CAS  Google Scholar 

  • Ljubetic A, Lapenta F, Gradisar H, Drobnak I, Aupic J, Strmsek Z, Lainscek D, Hafner-Bratkovic I, Majerle A, Krivec N, Bencina M, Pisanski T, Velickovic TC, Round A, Carazo JM, Melero R, Jerala R (2017) Design of coiled-coil protein-origami cages that self-assemble in vitro and in vivo. Nat Biotechnol 35:1094–1101

    CAS  PubMed  Google Scholar 

  • Lupas AN, Bassler J (2017) Coiled coils - a model system for the 21st century. Trends Biochem Sci 42:130–140

    Article  CAS  PubMed  Google Scholar 

  • Marcos E, Basanta B, Chidyausiku TM, Tang Y, Oberdorfer G, Liu G, Swapna GV, Guan R, Silva DA, Dou J, Pereira JH, Xiao R, Sankaran B, Zwart PH, Montelione GT, Baker D (2017) Principles for designing proteins with cavities formed by curved beta sheets. Science 355:201–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuura T, Ernst A, Zechel DL, Pluckthun A (2004) Combinatorial approaches to novel proteins. Chembiochem 5:177–182

    Article  CAS  PubMed  Google Scholar 

  • McCafferty J, Griffiths AD, Winter G, Chiswell DJ (1990) Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348:552–554

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto T, Kuribayashi M, Nagao S, Shomura Y, Higuchi Y, Hirota S (2015) Domain-swapped cytochrome cb(562) dimer and its nanocage encapsulating a Zn-SO4 cluster in the internal cavity. Chem Sci 6:7336–7342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyazaki N, Kiyose N, Akazawa Y, Takashima M, Hagihara Y, Inoue N, Matsuda T, Ogawa R, Inoue S, Ito Y (2015) Isolation and characterization of antigen-specific alpaca (Lama Pacos) VHH antibodies by biopanning followed by high-throughput sequencing. J Biochem 158:205–215

    Article  CAS  PubMed  Google Scholar 

  • Morimoto J, Hayashi Y, Iwasaki K, Suga H (2011) Flexizymes: their evolutionary history and the origin of catalytic function. Acc Chem Res 44:1359–1368

    Article  CAS  PubMed  Google Scholar 

  • Mou Y, Huang PS, Hsu FC, Huang SJ, Mayo SL (2015a) Computational design and experimental verification of a symmetric protein homodimer. Proc Natl Acad Sci U S A 112:10714–10719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mou Y, Yu JY, Wannier TM, Guo CL, Mayo SL (2015b) Computational design of co-assembling protein-DNA nanowires. Nature 525:230–233

    Article  CAS  PubMed  Google Scholar 

  • Murakami H, Ohta A, Ashigai H, Suga H (2006) A highly flexible tRNA acylation method for non-natural polypeptide synthesis. Nat Methods 3:357–359

    Article  CAS  PubMed  Google Scholar 

  • Nemoto N, Miyamoto-Sato E, Husimi Y, Yanagawa H (1997) In vitro virus: bonding of mRNA bearing puromycin at the 3′-terminal end to the C-terminal end of its encoded protein on the ribosome in vitro. FEBS Lett 414:405–408

    Article  CAS  PubMed  Google Scholar 

  • Nemoto N, Fukushima T, Kumachi S, Suzuki M, Nishigaki K, Kubo T (2014) Versatile C-terminal specific biotinylation of proteins using both a puromycin-linker and a cell-free translation system for studying high-throughput protein-molecule interactions. Anal Chem 86:8535–8540

    Article  CAS  PubMed  Google Scholar 

  • Niitsu A, Heal JW, Fauland K, Thomson AR, Woolfson DN (2017) Membrane-spanning α-helical barrels as tractable protein-design targets. Philos Trans R Soc B 372:20160213

  • Ogihara NL, Ghirlanda G, Bryson JW, Gingery M, DeGrado WF, Eisenberg D (2001) Design of three-dimensional domain-swapped dimers and fibrous oligomers. Proc Natl Acad Sci U S A 98:1404–1409

  • Packer MS, Liu DR (2015) Methods for the directed evolution of proteins. Nat Rev Genet 16:379–394

    Article  CAS  PubMed  Google Scholar 

  • Padilla JE, Colovos C, Yeates TO (2001) Nanohedra: using symmetry to design self assembling protein cages, layers, crystals, and filaments. Proc Natl Acad Sci U S A 98:2217–2221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Park K, Shen BW, Parmeggiani F, Huang PS, Stoddard BL, Baker D (2015) Control of repeat-protein curvature by computational protein design. Nat Struct Mol Biol 22:167–174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Parmeggiani F, Huang PS (2017) Designing repeat proteins: a modular approach to protein design. Curr Opin Struct Biol 45:116–123

    Article  CAS  PubMed  Google Scholar 

  • Passioura T, Suga H (2017) A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. Chem Commun 53:1931–1940

    Article  CAS  Google Scholar 

  • Patel SC, Hecht MH (2012) Directed evolution of the peroxidase activity of a de novo-designed protein. Protein Eng Des Sel 25:445–452

    Article  CAS  PubMed  Google Scholar 

  • Patel SC, Bradley LH, Jinadasa SP, Hecht MH (2009) Cofactor binding and enzymatic activity in an unevolved superfamily of de novo designed 4-helix bundle proteins. Protein Sci 18:1388–1400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pieters BJ, van Eldijk MB, Nolte RJ, Mecinovic J (2016) Natural supramolecular protein assemblies. Chem Soc Rev 45:24–39

    Article  CAS  PubMed  Google Scholar 

  • Reichen C, Hansen S, Pluckthun A (2014) Modular peptide binding: from a comparison of natural binders to designed armadillo repeat proteins. J Struct Biol 185:147–162

    Article  CAS  PubMed  Google Scholar 

  • Reichen C, Hansen S, Forzani C, Honegger A, Fleishman SJ, Zhou T, Parmeggiani F, Ernst P, Madhurantakam C, Ewald C, Mittl PR, Zerbe O, Baker D, Caflisch A, Pluckthun A (2016) Computationally designed armadillo repeat proteins for modular peptide recognition. J Mol Biol 428:4467–4489

    Article  CAS  PubMed  Google Scholar 

  • Richter F, Leaver-Fay A, Khare SD, Bjelic S, Baker D (2011) De novo enzyme design using Rosetta3. PLoS ONE 6:e19230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riechmann L, Winter G (2000) Novel folded protein domains generated by combinatorial shuffling of polypeptide segments. Proc Natl Acad Sci U S A 97:10068–10073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roberts RW, Szostak JW (1997) RNA-peptide fusions for the in vitro selection of peptides and proteins. Proc Natl Acad Sci U S A 94:12297–12302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rocklin GJ, Chidyausiku TM, Goreshnik I, Ford A, Houliston S, Lemak A, Carter L, Ravichandran R, Mulligan VK, Chevalier A, Arrowsmith CH, Baker D (2017) Global analysis of protein folding using massively parallel design, synthesis, and testing. Science 357:168–175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rothlisberger D, Khersonsky O, Wollacott AM, Jiang L, DeChancie J, Betker J, Gallaher JL, Althoff EA, Zanghellini A, Dym O, Albeck S, Houk KN, Tawfik DS, Baker D (2008) Kemp elimination catalysts by computational enzyme design. Nature 453:190–195

    Article  PubMed  CAS  Google Scholar 

  • Salgado EN, Ambroggio XI, Brodin JD, Lewis RA, Kuhlman B, Tezcan FA (2010a) Metal templated design of protein interfaces. Proc Natl Acad Sci U S A 107:1827–1832

    Article  CAS  PubMed  Google Scholar 

  • Salgado EN, Radford RJ, Tezcan FA (2010b) Metal-directed protein self-assembly. Acc Chem Res 43:661–672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sciore A, Su M, Koldewey P, Eschweiler JD, Diffley KA, Linhares BM, Ruotolo BT, Bardwell JC, Skiniotis G, Marsh EN (2016) Flexible, symmetry-directed approach to assembling protein cages. Proc Natl Acad Sci U S A 113:8681–8686

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Siegel JB, Zanghellini A, Lovick HM, Kiss G, Lambert AR, St Clair JL, Gallaher JL, Hilvert D, Gelb MH, Stoddard BL, Houk KN, Michael FE, Baker D (2010) Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction. Science 329:309–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith BA, Hecht MH (2011) Novel proteins: from fold to function. Curr Opin Chem Biol 15:421–426

    Article  CAS  PubMed  Google Scholar 

  • Smith BA, Mularz AE, Hecht MH (2015) Divergent evolution of a bifunctional de novo protein. Protein Sci 24:246–252

    Article  CAS  PubMed  Google Scholar 

  • Song WJ, Tezcan FA (2014) A designed supramolecular protein assembly with in vivo enzymatic activity. Science 346:1525–1528

    Article  CAS  PubMed  Google Scholar 

  • Sontz PA, Bailey JB, Ahn S, Tezcan FA (2015) A metal organic framework with spherical protein nodes: rational chemical design of 3D protein crystals. J Am Chem Soc 137:11598–11601

    Article  CAS  PubMed  Google Scholar 

  • Stapleton JA, Swartz JR (2010) Development of an in vitro compartmentalization screen for high-throughput directed evolution of [FeFe] hydrogenases. PLoS ONE 5:e15275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Strauch EM, Bernard SM, La D, Bohn AJ, Lee PS, Anderson CE, Nieusma T, Holstein CA, Garcia NK, Hooper KA, Ravichandran R, Nelson JW, Sheffler W, Bloom JD, Lee KK, Ward AB, Yager P, Fuller DH, Wilson IA, Baker D (2017) Computational design of trimeric influenza-neutralizing proteins targeting the hemagglutinin receptor binding site. Nat Biotechnol 35:667–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suzuki Y, Cardone G, Restrepo D, Zavattieri PD, Baker TS, Tezcan FA (2016) Self-assembly of coherently dynamic, auxetic, two-dimensional protein crystals. Nature 533:369–373

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thomas F, Burgess NC, Thomson AR, Woolfson DN (2016) Controlling the assembly of coiled-coil peptide Nanotubes. Angew Chem Int Ed 55:987–991

    Article  CAS  Google Scholar 

  • Thomson AR, Wood CW, Burton AJ, Bartlett GJ, Sessions RB, Brady RL, Woolfson DN (2014) Computational design of water-soluble alpha-helical barrels. Science 346:485–488

    Article  CAS  PubMed  Google Scholar 

  • Tinberg CE, Khare SD, Dou J, Doyle L, Nelson JW, Schena A, Jankowski W, Kalodimos CG, Johnsson K, Stoddard BL, Baker D (2013) Computational design of ligand-binding proteins with high affinity and selectivity. Nature 501:212–216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ueno S, Kimura S, Ichiki T, Nemoto N (2012) Improvement of a puromycin-linker to extend the selection target varieties in cDNA display method. J Biotechnol 162:299–302

    Article  CAS  PubMed  Google Scholar 

  • Urvoas A, Guellouz A, Valerio-Lepiniec M, Graille M, Durand D, Desravines DC, van Tilbeurgh H, Desmadril M, Minard P (2010) Design, production and molecular structure of a new family of artificial alpha-helicoidal repeat proteins (αRep) based on thermostable HEAT-like repeats. J Mol Biol 404:307–327

  • Urvoas A, Valerio-Lepiniec M, Minard P (2012) Artificial proteins from combinatorial approaches. Trends Biotechnol 30:512–520

    Article  CAS  PubMed  Google Scholar 

  • Uyeda A, Nakayama S, Kato Y, Watanabe H, Matsuura T (2016) Construction of an in vitro gene screening system of the E. Coli EmrE transporter using liposome display. Anal Chem 88:12028–12035

  • Varadamsetty G, Tremmel D, Hansen S, Parmeggiani F, Pluckthun A (2012) Designed armadillo repeat proteins: library generation, characterization and selection of peptide binders with high specificity. J Mol Biol 424:68–87

    Article  CAS  PubMed  Google Scholar 

  • Voet AR, Noguchi H, Addy C, Simoncini D, Terada D, Unzai S, Park SY, Zhang KY, Tame JR (2014) Computational design of a self-assembling symmetrical beta-propeller protein. Proc Natl Acad Sci U S A 111:15102–15107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voet AR, Noguchi H, Addy C, Zhang KY, Tame JR (2015) Biomineralization of a cadmium chloride Nanocrystal by a designed symmetrical protein. Angew Chem Int Ed 54:9857–9860

    Article  CAS  Google Scholar 

  • Votteler J, Ogohara C, Yi S, Hsia Y, Nattermann U, Belnap DM, King NP, Sundquist WI (2016) Designed proteins induce the formation of nanocage-containing extracellular vesicles. Nature 540:292–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe H, Honda S (2015) Adaptive assembly: maximizing the potential of a given functional peptide with a tailor-made protein scaffold. Chem Biol 22:1165–1173

    Article  CAS  PubMed  Google Scholar 

  • Watanabe H, Yamasaki K, Honda S (2014) Tracing primordial protein evolution through structurally guided stepwise segment elongation. J Biol Chem 289:3394–3404

    Article  CAS  PubMed  Google Scholar 

  • Wei Y, Kim S, Fela D, Baum J, Hecht MH (2003) Solution structure of a de novo protein from a designed combinatorial library. Proc Natl Acad Sci U S A 100:13270–13273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • West MW, Wang W, Patterson J, Mancias JD, Beasley JR, Hecht MH (1999) De novo amyloid proteins from designed combinatorial libraries. Proc Natl Acad Sci U S A 96:11211–11216

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Whitehead TA, Chevalier A, Song Y, Dreyfus C, Fleishman SJ, De Mattos C, Myers CA, Kamisetty H, Blair P, Wilson IA, Baker D (2012) Optimization of affinity, specificity and function of designed influenza inhibitors using deep sequencing. Nat Biotechnol 30:543–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson DS, Keefe AD, Szostak JW (2001) The use of mRNA display to select high-affinity protein-binding peptides. Proc Natl Acad Sci U S A 98:3750–3755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wood CW, Woolfson DN (2017) CCBuilder 2.0: powerful and accessible coiled-coil modeling. Protein Sci (in press) doi:10.1002/pro.3279

  • Wood CW, Bruning M, Ibarra AA, Bartlett GJ, Thomson AR, Sessions RB, Brady RL, Woolfson DN (2014) CCBuilder: an interactive web-based tool for building, designing and assessing coiled-coil protein assemblies. Bioinformatics 30:3029–3035

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Woolfson DN, Bartlett GJ, Bruning M, Thomson AR (2012) New currency for old rope: from coiled-coil assemblies to α-helical barrels. Curr Opin Struct Biol 22:432–441

  • Woolfson DN, Bartlett GJ, Burton AJ, Heal JW, Niitsu A, Thomson AR, Wood CW (2015) De novo protein design: how do we expand into the universe of possible protein structures? Curr Opin Struct Biol 33:16–26

  • Wrenbeck EE, Faber MS, Whitehead TA (2017) Deep sequencing methods for protein engineering and design. Curr Opin Struct Biol 45:36–44

    Article  CAS  PubMed  Google Scholar 

  • Yagi S, Akanuma S, Yamagishi M, Uchida T, Yamagishi A (2016) De novo design of protein–protein interactions through modification of inter-molecular helix–helix interface residues. Biochim Biophys Acta 1864:479–487

  • Yagi S, Akanuma S, Yamagishi A (2017) Creation of artificial protein–protein interactions using α-helices as interface. Biophys Rev. https://doi.org/10.1007/s12551-017-0352-9

  • Yamagishi Y, Shoji I, Miyagawa S, Kawakami T, Katoh T, Goto Y, Suga H (2011) Natural product-like macrocyclic N-methyl-peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library. Chem Biol 18:1562–1570

    Article  CAS  PubMed  Google Scholar 

  • Yamaguchi J, Naimuddin M, Biyani M, Sasaki T, Machida M, Kubo T, Funatsu T, Husimi Y, Nemoto N (2009) cDNA display: a novel screening method for functional disulfide-rich peptides by solid-phase synthesis and stabilization of mRNA-protein fusions. Nucleic Acids Res 37:e108

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Yeates TO, Liu Y, Laniado J (2016) The design of symmetric protein nanomaterials comes of age in theory and practice. Curr Opin Struct Biol 39:134–143

    Article  PubMed  CAS  Google Scholar 

  • Yoshimoto N, Tatematsu K, Iijima M, Niimi T, Maturana AD, Fujii I, Kondo A, Tanizawa K, Kuroda S (2014) High-throughput de novo screening of receptor agonists with an automated single-cell analysis and isolation system. Sci Rep 4:4242

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zanghellini A (2014) de novo computational enzyme design. Curr Opin Biotechnol 29:132–138

    Article  CAS  PubMed  Google Scholar 

  • Zhu B, Mizoguchi T, Kojima T, Nakano H (2015) Ultra-high-throughput screening of an in vitro-synthesized horseradish peroxidase displayed on microbeads using cell sorter. PLoS ONE 10:e0127479

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

I thank all colleagues and collaborators, especially, Dr. Naoya Kobayashi and Dr. Nobuyasu Koga at Institute for Molecular Science (IMS), Prof. Michael H. Hecht at Princeton University, Dr. Shinya Honda at Advanced Industrial Science and Technology, and Dr. Tomoaki Matsuura at Osaka University for their help and valuable discussion. I apologize to the protein designers and protein engineers whose works I was unable to acknowledge due to space and scope limitations. This work was supported by JSPS KAKENHI Grant Numbers JP16K05841 and JP16H00761 (an Innovative Area, “Dynamical Ordering and Integrated Functions”), and Joint Research by IMS.

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  1. Department of Applied Biology, Faculty of Textile Science and Technology, Shinshu University, Ueda, Nagano 386-8567, Japan

    Ryoichi Arai

  2. Department of Supramolecular Complexes, Research Center for Fungal and Microbial Dynamism, Shinshu University, Minamiminowa, Nagano 399-4598, Japan

    Ryoichi Arai

  3. Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Nagano 390-8621, Japan

    Ryoichi Arai

  4. Division of Structural and Synthetic Biology, RIKEN Center for Life Science Technologies, Tsurumi, Yokohama, Kanagawa 230-0045, Japan

    Ryoichi Arai

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This article is part of a Special Issue on ‘Biomolecules to Bio-nanomachines - Fumio Arisaka 70th Birthday’ edited by Damien Hall, Junichi Takagi and Haruki Nakamura.

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Arai, R. Hierarchical design of artificial proteins and complexes toward synthetic structural biology. Biophys Rev 10, 391–410 (2018). https://doi.org/10.1007/s12551-017-0376-1

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