Abstract
Statistical analysis of a protein multiple sequence alignment can reveal groups of positions that undergo interdependent mutations throughout evolution. At these so-called correlated positions, only certain combinations of amino acids appear to be viable for maintaining proper folding, stability, catalytic activity or specificity. Therefore, it is often speculated that they could be interesting guides for semi-rational protein engineering purposes. Because they are a fingerprint from protein evolution, their analysis may provide valuable insight into a protein’s structure or function and furthermore, they may also be suitable target positions for mutagenesis. Unfortunately, little is currently known about the properties of these correlation networks and how they should be used in practice. This review summarises the recent findings, opportunities and pitfalls of the concept.
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References
Altschuh D, Vernet T, Berti P, Moras D, Nagai K (1988) Coordinated amino acid changes in homologous protein families. Protein Eng Des Sel 2:193–199
Bednar D, Beerens K, Sebestova E, Bendl J, Khare S, Chaloupkova R, Prokop Z, Brezovsky J, Baker D, Damborsky J (2015) FireProt: energy- and evolution-based computational design of thermostable multiple-point mutants. PLoS Comput Biol 11:1–20
Bendl J, Stourac J, Sebestova E, Vavra O, Musil M, Brezovsky J, Damborsky J (2016) HotSpot Wizard 2.0: automated design of site-specific mutations and smart libraries in protein engineering. Nucleic Acids Res. doi:10.1093/nar/gkw416
Bornscheuer UT, Huisman GW, Kazlauskas RJ, Lutz S, Moore JC, Robins K (2012) Engineering the third wave of biocatalysis. Nature 485:185–194
Chakrabarti S, Panchenko AR (2009) Coevolution in defining the functional specificity. Proteins Struct Funct Bioinform 75:231–240
Chen Z, Meyer W, Rappert S, Sun J, Zeng AP (2011) Coevolutionary analysis enabled rational deregulation of allosteric enzyme inhibition in Corynebacterium glutamicum for lysine production. Appl Environ Microbiol 77:4352–4360
Chen Z, Rappert S, Sun J, Zeng AP (2011) Integrating molecular dynamics and co-evolutionary analysis for reliable target prediction and deregulation of the allosteric inhibition of aspartokinase for amino acid production. J Biotechnol 154:248–254
Currin A, Swainston N, Day PJ, Kell DB (2015) Synthetic biology for the directed evolution of protein biocatalysts: navigating sequence space intelligently. Chem Soc Rev 44:1172–1239
Dalby PA (2011) Strategy and success for the directed evolution of enzymes. Curr Opin Struct Biol 21:473–480
Dietrich S, Borst N, Schlee S, Schneider D, Janda J, Sterner R, Merkl R (2012) Experimental assessment of the importance of amino acid positions identified by an entropy-based correlation analysis of multiple-sequence alignments. Biochemistry 51:5633–5641
Dill KA, MacCallum JL (2012) The protein-folding problem, 50 years on. Science 338:1042–1046
Van Durme J, Delgado J, Stricher F, Serrano L, Schymkowitz J, Rousseau F (2011) A graphical interface for the FoldX forcefield. Bioinformatics 27:1711–1712
Ehrlich PR, Raven PH (1964) Butterflies and plants: a study in coevolution. Evolution 18:586–608
Eijsink VGH, Bjørk A, Gåseidnes S, Sirevåg R, Synstad B, van den Burg B, Vriend G (2004) Rational engineering of enzyme stability. J Biotechnol 113:105–120
Eijsink VGH, Gåseidnes S, Borchert TV, van den Burg B (2005) Directed evolution of enzyme stability. Biomol Eng 22:21–30
Gloor GB, Martin LC, Wahl LM, Dunn SD (2005) Mutual information in protein multiple sequence alignments reveals two classes of coevolving positions. Biochemistry 44:7156–7165
Göbel U, Sander C, Schneider R, Valencia A (1994) Correlated mutations and residue contacts in proteins. Proteins 18:309–317
Goldsmith M, Tawfik DS (2012) Directed enzyme evolution: beyond the low-hanging fruit. Curr Opin Struct Biol 22:406–412
Gregoret LM, Sauer RT (1993) Additivity of mutant effects assessed by binomial mutagenesis. Proc Natl Acad Sci USA 90:4246–4250
Halabi N, Rivoire O, Leibler S, Ranganathan R (2009) Protein sectors: evolutionary units of three-dimensional structure. Cell 138:774–786
Hayat S, Sander C, Marks DS, Elofsson A (2015) All-atom 3D structure prediction of transmembrane β-barrel proteins from sequences. Proc Natl Acad Sci USA 112:5413–5548
Hopf TA, Morinaga S, Ihara S, Touhara K, Marks DS, Benton R (2015) Amino acid coevolution reveals three-dimensional structure and functional domains of insect odorant receptors. Nat Commun 6:6077
Hopf TA, Schärfe CPI, Rodrigues JPGLM, Green AG, Kohlbacher O, Sander C, Bonvin AMJJ, Marks DS (2014) Sequence co-evolution gives 3D contacts and structures of protein complexes. Elife 3:e03430
Joosten HJ, Han Y, Niu W, Vervoort J, Dunaway-Mariano D, Schaap PJ (2008) Identification of fungal oxaloacetate hydrolyase within the isocitrate lyase/PEP mutase enzyme superfamily using a sequence marker-based method. Proteins Struct Funct Bioinform 70:157–166
de Juan D, Pazos F, Valencia A (2013) Emerging methods in protein co-evolution. Nat Rev Genet 14:249–261
Kazlauskas RJ, Bornscheuer UT (2009) Finding better protein engineering strategies. Nat Chem Biol 5:526–529
Kellogg EH, Leaver-Fay A, Baker D (2011) Role of conformational sampling in computing mutation-induced changes in protein structure and stability. Proteins Struct Funct Bioinform 79:830–838
Kortemme T, Baker D (2004) Computational design of protein-protein interactions. Curr Opin Chem Biol 8:91–97
Kuipers RKP, Joosten H-J, Verwiel E, Paans S, Akerboom J, van der Oost J, Leferink NGH, van Berkel WJH, Vriend G, Schaap PJ (2009) Correlated mutation analyses on super-family alignments reveal functionally important residues. Proteins Struct Funct Bioinform 76:608–616
Livesay DR, Kreth KE, Fodor AA (2012) A critical evaluation of correlated mutation algorithms and coevolution within allosteric mechanisms. Methods Mol Biol 286:385–398
Lockless SW, Ranganathan R (1999) Evolutionarily conserved pathways of energetic connectivity in protein families. Science 286:295–299
Lovell SC, Robertson DL (2010) An integrated view of molecular coevolution in protein-protein interactions. Mol Biol Evol 27:2567–2575
Lutz S (2010) Beyond directed evolution: semi-rational protein engineering and design. Curr Opin Biotechnol 21:734–743
Marks DS, Colwell LJ, Sheridan R, Hopf TA, Pagnani A, Zecchina R, Sander C (2011) Protein 3D structure computed from evolutionary sequence variation. PLoS One 6:e28766
Marks DS, Hopf TA, Sander C (2012) Protein structure prediction from sequence variation. Nat Biotechnol 30:1072–1080
McLaughlin RN, Poelwijk FJ, Raman A, Gosal WS, Ranganathan R (2012) The spatial architecture of protein function and adaptation. Nature 491:138–142
McMurrough TA, Dickson RJ, Thibert SMF, Gloor GB, Edgell DR (2014) Control of catalytic efficiency by a coevolving network of catalytic and noncatalytic residues. Proc Natl Acad Sci 111:E2376–E2383
Miyazaki K, Arnold FH (1999) Exploring nonnatural evolutionary pathways by saturation mutagenesis: rapid improvement of protein function. J Mol Evol 49:716–720
Morley KL, Kazlauskas RJ (2005) Improving enzyme properties: when are closer mutations better? Trends Biotechnol 23:231–237
Neher E (1994) How frequent are correlated changes in families of protein sequences? Proc Natl Acad Sci USA 91:98–102
Nobili A, Tao Y, Pavlidis IV, van den Bergh T, Joosten H-J, Tan T, Bornscheuer UT (2015) Simultaneous use of in silico design and a correlated mutation network as a tool to efficiently guide enzyme engineering. Chembiochem 16:805–810
Pazos F, Helmer-Citterich M, Ausiello G, Valencia A (1997) Correlated mutations contain information about protein-protein interaction. J Mol Biol 271:511–523
Raman AS, White KI, Ranganathan R (2016) Origins of allostery and evolvability in proteins: a case study. Cell. doi:10.1016/j.cell.2016.05.047
Reetz M, Kahakeaw D, Lohmer R (2008) Addressing the numbers problem in directed evolution. Chembiochem 9:1797–1804
Reetz MT (2013) The importance of additive and non-additive mutational effects in protein engineering. Angew Chem Int Ed Engl 52:2658–2666
Reetz MT, Prasad S, Carballeira JD, Gumulya Y, Bocola M (2010) Iterative saturation mutagenesis accelerates laboratory evolution of enzyme stereoselectivity: rigorous comparison with traditional methods. J Am Chem Soc 132:9144–9152
Reetz MT, Wang L-W, Bocola M (2006) Directed evolution of enantioselective enzymes: iterative cycles of CASTing for probing protein-sequence space. Angew Chem Int Ed Engl 45:1236–1241
Salverda MLM, Dellus E, Gorter FA, Debets AJM, van der Oost J, Hoekstra RF, Tawfik DS, de Visser JAGM (2011) Initial mutations direct alternative pathways of protein evolution. PLoS Genet 7:e1001321
Shindyalov IN, Kolchanov NA, Sander C (1994) Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations? Protein Eng 7:349–358
Soskine M, Tawfik DS (2010) Mutational effects and the evolution of new protein functions. Nat Rev Genet 11:572–582
Stiffler MA, Hekstra DR, Ranganathan R (2015) Evolvability as a function of purifying selection in TEM-1 β-lactamase. Cell 160:882–892
Strafford J, Payongsri P, Hibbert EG, Morris P, Batth SS, Steadman D, Smith MEB, Ward JM, Hailes HC, Dalby PA (2012) Directed evolution to re-adapt a co-evolved network within an enzyme. J Biotechnol 157:237–245
Sullivan BJ, Nguyen T, Durani V, Mathur D, Rojas S, Thomas M, Syu T, Magliery TJ (2012) Stabilizing proteins from sequence statistics: the interplay of conservation and correlation in triosephosphate isomerase stability. J Mol Biol 420:384–399
Sutto L, Marsili S, Valencia A, Gervasio FL (2015) From residue coevolution to protein conformational ensembles and functional dynamics. Proc Natl Acad Sci USA 112:13567–13572
Taylor WR, Hatrick K (1994) Compensating changes in protein multiple sequence alignments. Protein Eng 7:341–348
Turner NJ (2009) Directed evolution drives the next generation of biocatalysts. Nat Chem Biol 5:567–573
Verges A, Cambon E, Barbe S, Salamone S, Le Guen Y, Moulis C, Mulard LA, Remaud-Siméon M, André I (2015) Computer-aided engineering of a transglycosylase for the glucosylation of an unnatural disaccharide of relevance for bacterial antigen synthesis. ACS Catal 5:1186–1198
Wang C, Huang R, He B, Du Q (2012) Improving the thermostability of alpha-amylase by combinatorial coevolving-site saturation mutagenesis. BMC Bioinform 13:263
Zou T, Risso VA, Gavira JA, Sanchez-Ruiz JM, Ozkan SB (2014) Evolution of conformational dynamics determines the conversion of a promiscuous generalist into a specialist enzyme. Mol Biol Evol 32:132–143
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The authors wish to thank the Fund for Scientific Research-Flanders (FWO-Vlaanderen) for financial support (doctoral scholarship for JF).
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Franceus, J., Verhaeghe, T. & Desmet, T. Correlated positions in protein evolution and engineering. J Ind Microbiol Biotechnol 44, 687–695 (2017). https://doi.org/10.1007/s10295-016-1811-1
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DOI: https://doi.org/10.1007/s10295-016-1811-1