Dynamics and constraints of enzyme evolution

Journal of Experimental Zoology Part B: Molecular and Developmental Evolution

Volumn 322, Issue 7, 2014, Pages 468-487

  Kaltenbach, Miriam ^a   Tokuriki, Nobuhiko ^a  

^a UNIVERSITY OF BRITISH COLUMBIA   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ENZYME; PROTEIN;

CHEMISTRY; EPISTASIS; GENETICS; METABOLISM; MOLECULAR EVOLUTION; MUTAGENESIS; MUTATION;

ENZYMES; EPISTASIS, GENETIC; EVOLUTION, MOLECULAR; MUTAGENESIS; MUTATION; PROTEINS;

EID: 84908606115     PISSN: 15525007     EISSN: 15525015     Source Type: Journal    
DOI: 10.1002/jez.b.22562     Document Type: Review

References (175)

1. Ackermann M, Beyer A. 2012. Systematic detection of epistatic interactions based on allele pair frequencies. PLoS Genet 8:e1002463.
2. Afriat L, Roodveldt C, Manco G, Tawfik DS. 2006. The latent promiscuity of newly identified microbial lactonases is linked to a recently diverged phosphotriesterase. Biochemistry 45:13677-13686.
3. Afriat-Jurnou L, Jackson CJ, Tawfik DS. 2012. Reconstructing a missing link in the evolution of a recently diverged phosphotriesterase by active-site loop remodeling. Biochemistry 51:6047-6055.
4. Aharoni A, Gaidukov L, Khersonsky O, et al. 2005. The 'evolvability' of promiscuous protein functions. Nat Genet 37:73-76.
5. Aita T, Husimi Y. 1998. Adaptive walks by the fittest among finite random mutants on a Mt. Fuji-type Fitness Landscape. J Theor Biol 193:383-405.
6. Amitai G, Gupta RD, Tawfik DS. 2007. Latent evolutionary potentials under the neutral mutational drift of an enzyme. HFSP J 1:67-78.
7. Arjan JA, Visser M, Zeyl CW, et al. 1999. Diminishing returns from mutation supply rate in asexual populations. Science 283:404-406.
8. Armstrong RN. 2000. Mechanistic diversity in a metalloenzyme superfamily. Biochemistry 39:13625-13632.
9. Aylor DL, Zeng ZB. 2008. From classical genetics to quantitative genetics to systems biology: modeling epistasis. PLoS Genet 4:e1000029.
10. Babtie A, Tokuriki N, Hollfelder F. 2010. What makes an enzyme promiscuous? Curr Opin Chem Biol 14:200-207.
11. Bar-Even A, Noor E, Savir Y, et al. 2011. The moderately efficient enzyme: evolutionary and physicochemical trends shaping enzyme parameters. Biochemistry 50:4402-4410.
12. Bar-Rogovsky H, Hugenmatter A, Tawfik DS. 2013. The evolutionary origins of detoxifying enzymes: the mammalian serum paraoxonases (PONs) relate to bacterial homoserine lactonases. J Biol Chem 288:23914-23927.
13. Barona-Gomez F, Hodgson DA. 2003. Occurrence of a putative ancient-like isomerase involved in histidine and tryptophan biosynthesis. EMBO Rep 4:296-300.
14. Bebrone C. 2007. Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem Pharmacol 74:1686-1701.
15. Bershtein S, Tawfik DS. 2008. Ohno's model revisited: measuring the frequency of potentially adaptive mutations under various mutational drifts. Mol Biol Evol 25:2311-2318.
16. Bershtein S, Segal M, Bekerman R, Tokuriki N, Tawfik DS. 2006. Robustness-epistasis link shapes the fitness landscape of a randomly drifting protein. Nature 444:929-932.
17. Bershtein S, Goldin K, Tawfik DS. 2008. Intense neutral drifts yield robust and evolvable consensus proteins. J Mol Biol 379:1029-1044.
18. Bloom JD, Arnold FH. 2009. In the light of directed evolution: pathways of adaptive protein evolution. Proc Natl Acad Sci USA 106(Suppl 1):9995-10000.
19. Bloom JD, Glassman MJ. 2009. Inferring stabilizing mutations from protein phylogenies: application to influenza hemagglutinin. PLoS Comput Biol 5:e1000349.
20. Bloom JD, Silberg JJ, Wilke CO, et al. 2005. Thermodynamic prediction of protein neutrality. Proc Natl Acad Sci USA 102:606-611.
21. Bloom JD, Romero PA, Lu Z, Arnold FH. 2007. Neutral genetic drift can alter promiscuous protein functions, potentially aiding functional evolution. Biol Direct 2:17.
22. Bloom JD, Gong LI, Baltimore D. 2010. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328:1272-1275.
23. Bolon DN, Mayo SL. 2001. Enzyme-like proteins by computational design. Proc Natl Acad Sci USA 98:14274-14279.
24. Bommarius AS, Broering JM, Chaparro-Riggers JF, Polizzi KM. 2006. High-throughput screening for enhanced protein stability. Curr Opin Biotechnol 17:606-610.
25. Bonhoeffer S, Chappey C, Parkin NT, Whitcomb JM, Petropoulos CJ. 2004. Evidence for positive epistasis in HIV-1. Science 306:1547-1550.
26. Breen MS, Kemena C, Vlasov PK, Notredame C, Kondrashov FA. 2012. Epistasis as the primary factor in molecular evolution. Nature 490:535-538.
27. Bridgham JT, Ortlund EA, Thornton JW. 2009. An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. Nature 461:515-519.
28. Brown NG, Pennington JM, Huang W, Ayvaz T, Palzkill T. 2010a. Multiple global suppressors of protein stability defects facilitate the evolution of extended-spectrum TEM beta-lactamases. J Mol Biol 404:832-846.
29. Brown KM, Costanzo MS, Xu W, et al. 2010b. Compensatory mutations restore fitness during the evolution of dihydrofolate reductase. Mol Biol Evol 27:2682-2690.
30. Cabrita LD, Gilis D, Robertson AL, et al. 2007. Enhancing the stability and solubility of TEV protease using in silico design. Protein Sci 16:2360-2367.
31. Carbone MN, Arnold FH. 2007. Engineering by homologous recombination: exploring sequence and function within a conserved fold. Curr Opin Struct Biol 17:454-459.
32. Carneiro M, Hartl DL. 2010. Colloquium papers: adaptive landscapes and protein evolution. Proc Natl Acad Sci USA 107(Suppl 1):1747-1751.
33. Chen Z, Zhao H. 2005. Rapid creation of a novel protein function by in vitro coevolution. J Mol Biol 348:1273-1282.
34. Chou HH, Chiu HC, Delaney NF, Segre D, Marx CJ. 2011. Diminishing returns epistasis among beneficial mutations decelerates adaptation. Science 332:1190-1192.
35. Collins CH, Leadbetter JR, Arnold FH. 2006. Dual selection enhances the signaling specificity of a variant of the quorum-sensing transcriptional activator LuxR. Nat Biotechnol 24:708-712.
36. Conant GC, Wolfe KH. 2008. Turning a hobby into a job: how duplicated genes find new functions. Nat Rev Genet 9:938-950.
37. Copley SD. 2009. Evolution of efficient pathways for degradation of anthropogenic chemicals. Nat Chem Biol 5:559-566.
38. Costanzo MS, Brown KM, Hartl DL. 2011. Fitness trade-offs in the evolution of dihydrofolate reductase and drug resistance in Plasmodium falciparum. PLoS ONE 6:e19636.
39. Dalby PA. 2011. Strategy and success for the directed evolution of enzymes. Curr Opin Struct Biol 21:473-480.
40. D'Ari R, Casadesus J. 1998. Underground metabolism. Bioessays 20:181-186.
41. Dawid A, Kiviet DJ, Kogenaru M, de Vos M, Tans SJ. 2010. Multiple peaks and reciprocal sign epistasis in an empirically determined genotype-phenotype landscape. Chaos 20:026105.
42. de Visser JA, Cooper TF, Elena SF. 2011. The causes of epistasis. Proc Biol Sci 278:3617-3624.
43. Dean AM, Thornton JW. 2007. Mechanistic approaches to the study of evolution: the functional synthesis. Nat Rev Genet 8:675-688.
44. Dean AM, Dykhuizen DE, Hartl DL. 1988. Fitness effects of amino acid replacements in the beta-galactosidase of Escherichia coli. Mol Biol Evol 5:469-485.
45. Dellus-Gur E, Toth-Petroczy A, Elias M, Tawfik DS. 2013. What makes a protein fold amenable to functional innovation? Fold polarity and stability trade-offs. J Mol Biol 425:2609-2621.
46. DePristo MA, Weinreich DM, Hartl DL. 2005. Missense meanderings in sequence space: a biophysical view of protein evolution. Nat Rev Genet 6:678-687.
47. DePristo MA, Hartl DL, Weinreich DM. 2007. Mutational reversions during adaptive protein evolution. Mol Biol Evol 24:1608-1610.
48. Dickinson BC, Leconte AM, Allen B, Esvelt KM, Liu DR. 2013. Experimental interrogation of the path dependence and stochasticity of protein evolution using phage-assisted continuous evolution. Proc Natl Acad Sci USA 110:9007-9012.
49. Dill KA. 1997. Additivity principles in biochemistry. J Biol Chem 272:701-704.
50. Doyon JB, Pattanayak V, Meyer CB, Liu DR. 2006. Directed evolution and substrate specificity profile of homing endonuclease I-SceI. J Am Chem Soc 128:2477-2484.
51. Dykhuizen DE, Dean AM, Hartl DL. 1987. Metabolic flux and fitness. Genetics 115:25-31.
52. Elena SF, Lenski RE. 2003. Evolution experiments with microorganisms: the dynamics and genetic bases of adaptation. Nat Rev Genet 4:457-469.
53. Esvelt KM, Carlson JC, Liu DR. 2011. A system for the continuous directed evolution of biomolecules. Nature 472:499-503.
54. Fasan R, Meharenna YT, Snow CD, Poulos TL, Arnold FH. 2008. Evolutionary history of a specialized p450 propane monooxygenase. J Mol Biol 383:1069-1080.
55. Flynn KM, Cooper TF, Moore FB, Cooper VS. 2013. The environment affects epistatic interactions to alter the topology of an empirical fitness landscape. PLoS Genet 9:e1003426.
56. Furnham N, Sillitoe I, Holliday GL, et al. 2012. Exploring the evolution of novel enzyme functions within structurally defined protein superfamilies. PLoS Comput Biol 8:e1002403.
57. Gerlt JA, Allen KN, Almo SC, et al. 2011. The enzyme function initiative. Biochemistry 50:9950-9962.
58. Gerlt JA, Babbitt PC, Jacobson MP, Almo SC. 2012. Divergent evolution in enolase superfamily: strategies for assigning functions. J Biol Chem 287:29-34.
59. Giger L, Caner S, Obexer R, et al. 2013. Evolution of a designed retro-aldolase leads to complete active site remodeling. Nat Chem Biol 9:494-498.
60. Glasner ME, Gerlt JA, Babbitt PC. 2006. Evolution of enzyme superfamilies. Curr Opin Chem Biol 10:492-497.
61. Gong LI, Suchard MA, Bloom JD. 2013. Stability-mediated epistasis constrains the evolution of an influenza protein. Elife 2:e00631.
62. Gould SJ. 1977. The return of hopeful monsters. Nat Hist 86:30.
63. Gould SM, Tawfik DS. 2005. Directed evolution of the promiscuous esterase activity of carbonic anhydrase II. Biochemistry 44:5444-5452.
64. Griswold KE, Kawarasaki Y, Ghoneim N, et al. 2005. Evolution of highly active enzymes by homology-independent recombination. Proc Natl Acad Sci USA 102:10082-10087.
65. Gumulya Y, Reetz MT. 2011. Enhancing the thermal robustness of an enzyme by directed evolution: least favorable starting points and inferior mutants can map superior evolutionary pathways. Chembiochem 12:2502-2510.
66. Hall BG. 2002. Predicting evolution by in vitro evolution requires determining evolutionary pathways. Antimicrob Agents Chemother 46:3035-3038.
67. Hall BG. 2004. Predicting the evolution of antibiotic resistance genes. Nat Rev Microbiol 2:430-435.
68. Harms MJ, Thornton JW. 2013. Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Nat Rev Genet 14:559-571.
69. Hartl DL, Dykhuizen DE, Dean AM. 1985. Limits of adaptation: the evolution of selective neutrality. Genetics 111:655-674.
70. Hayden EJ, Ferrada E, Wagner A. 2011. Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme. Nature 474:92-95.
71. Huang R, Hippauf F, Rohrbeck D, et al. 2012. Enzyme functional evolution through improved catalysis of ancestrally nonpreferred substrates. Proc Natl Acad Sci USA 109:2966-2971.
72. Hult K, Berglund P. 2007. Enzyme promiscuity: mechanism and applications. Trends Biotechnol 25:231-238.
73. Iffland A, Gendreizig S, Tafelmeyer P, Johnsson K. 2001. Changing the substrate specificity of cytochrome c peroxidase using directed evolution. Biochem Biophys Res Commun 286:126-132.
74. Innan H, Kondrashov F. 2010. The evolution of gene duplications: classifying and distinguishing between models. Nat Rev Genet 11:97-108.
75. Jacob F. 1977. Evolution and tinkering. Science 196:1161-1166.
76. Jensen RA. 1976. Enzyme recruitment in evolution of new function. Annu Rev Microbiol 30:409-425.
77. Jones DD. 2005. Triplet nucleotide removal at random positions in a target gene: the tolerance of TEM-1 beta-lactamase to an amino acid deletion. Nucleic Acids Res 33:e80.
78. Kachanovsky DE, Filler S, Isaacson T, Hirschberg J. 2012. Epistasis in tomato color mutations involves regulation of phytoene synthase 1 expression by cis-carotenoids. Proc Natl Acad Sci USA 109:19021-19026.
79. Kauffman S, Levin S. 1987. Towards a general theory of adaptive walks on rugged landscapes. J Theor Biol 128:11-45.
80. Kawecki TJ, Lenski RE, Ebert D, et al. 2012. Experimental evolution. Trends Ecol Evol 27:547-560.
81. Khan AI, Dinh DM, Schneider D, Lenski RE, Cooper TF. 2011. Negative epistasis between beneficial mutations in an evolving bacterial population. Science 332:1193-1196.
82. Khersonsky O, Tawfik DS. 2010. Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471-505.
83. Khersonsky O, Roodveldt C, Tawfik DS. 2006. Enzyme promiscuity: evolutionary and mechanistic aspects. Curr Opin Chem Biol 10:498-508.
84. Kim J, Kershner JP, Novikov Y, Shoemaker RK, Copley SD. 2010. Three serendipitous pathways in E. coli can bypass a block in pyridoxal-5′-phosphate synthesis. Mol Syst Biol 6:436.
85. Kipnis Y, Dellus-Gur E, Tawfik DS. 2012. TRINS: a method for gene modification by randomized tandem repeat insertions. Protein Eng Des Sel 25:437-444.
86. Kiss G, Celebi-Olcum N, Moretti R, Baker D, Houk KN. 2013. Computational enzyme design. Angew Chem Int Ed Engl 52:5700-5725.
87. Kogenaru M, de Vos MG, Tans SJ. 2009. Revealing evolutionary pathways by fitness landscape reconstruction. Crit Rev Biochem Mol Biol 44:169-174.
88. Kondrashov FA, Koonin EV. 2004. A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications. Trends Genet 20:287-290.
89. Koonin EV, Wolf YI. 2010. Constraints and plasticity in genome and molecular-phenome evolution. Nat Rev Genet 11:487-498.
90. Kouyos RD, Leventhal GE, Hinkley T, et al. 2012. Exploring the complexity of the HIV-1 fitness landscape. PLoS Genet 8:e1002551.
91. Kryazhimskiy S, Dushoff J, Bazykin GA, Plotkin JB. 2011. Prevalence of epistasis in the evolution of influenza A surface proteins. PLoS Genet 7:e1001301.
92. Kuliopulos A, Talalay P, Mildvan AS. 1990. Combined effects of two mutations of catalytic residues on the ketosteroid isomerase reaction. Biochemistry 29:10271-10280.
93. Kvitek DJ, Sherlock G. 2011. Reciprocal sign epistasis between frequently experimentally evolved adaptive mutations causes a rugged fitness landscape. PLoS Genet 7:e1002056.
94. Lehmann M, Pasamontes L, Lassen SF, Wyss M. 2000. The consensus concept for thermostability engineering of proteins. Biochim Biophys Acta 1543:408-415.
95. Lobkovsky AE, Koonin EV. 2012. Replaying the tape of life: quantification of the predictability of evolution. Front Genet 3:246.
96. Loewe L. 2012. How evolutionary systems biology will help understand adaptive landscapes and distributions of mutational effects. Adv Exp Med Biol 751:399-410.
97. Lozovsky ER, Chookajorn T, Brown KM, et al. 2009. Stepwise acquisition of pyrimethamine resistance in the malaria parasite. Proc Natl Acad Sci USA 106:12025-12030.
98. Lunzer M, Miller SP, Felsheim R, Dean AM. 2005. The biochemical architecture of an ancient adaptive landscape. Science 310:499-501.
99. Lunzer M, Golding GB, Dean AM. 2010. Pervasive cryptic epistasis in molecular evolution. PLoS Genet 6:e1001162.
100. MacLean RC, Perron GG, Gardner A. 2010. Diminishing returns from beneficial mutations and pervasive epistasis shape the fitness landscape for rifampicin resistance in Pseudomonas aeruginosa. Genetics 186:1345-1354.
101. Martin G, Elena SF, Lenormand T. 2007. Distributions of epistasis in microbes fit predictions from a fitness landscape model. Nat Genet 39:555-560.
102. Matsumura I, Ellington AD. 2001. In vitro evolution of beta-glucuronidase into a beta-galactosidase proceeds through non-specific intermediates. J Mol Biol 305:331-339.
103. Matsuura T, Miyai K, Trakulnaleamsai S, et al. 1999. Evolutionary molecular engineering by random elongation mutagenesis. Nat Biotechnol 17:58-61.
104. Mayer S, Rudiger S, Ang HC, Joerger AC, Fersht AR. 2007. Correlation of levels of folded recombinant p53 in escherichia coli with thermodynamic stability in vitro. J Mol Biol 372:268-276.
105. McLaughlin RN Jr, Poelwijk FJ, Raman A, Gosal WS, Ranganathan R. 2012. The spatial architecture of protein function and adaptation. Nature 491:138-142.
106. McLoughlin SY, Copley SD. 2008. A compromise required by gene sharing enables survival: implications for evolution of new enzyme activities. Proc Natl Acad Sci USA 105:13497-13502.
107. Mehta MM, Liu S, Silberg JJ. 2012. A transposase strategy for creating libraries of circularly permuted proteins. Nucleic Acids Res 40:e71.
108. Meier MM, Rajendran C, Malisi C, et al. 2013. Molecular engineering of organophosphate hydrolysis activity from a weak promiscuous lactonase template. J Am Chem Soc 135:11670-11677.
109. Melancon CE III, Schultz PG. 2009. One plasmid selection system for the rapid evolution of aminoacyl-tRNA synthetases. Bioorg Med Chem Lett 19:3845-3847.
110. Michalakis Y, Roze D. 2004. Evolution. Epistasis in RNA viruses. Science 306:1492-1493.
111. Miralles R, Moya A, Elena SF. 2000. Diminishing returns of population size in the rate of RNA virus adaptation. J Virol 74:3566-3571.
112. Nam H, Lewis NE, Lerman JA, et al. 2012. Network context and selection in the evolution to enzyme specificity. Science 337:1101-1104.
113. Nasvall J, Sun L, Roth JR, Andersson DI. 2012. Real-time evolution of new genes by innovation, amplification, and divergence. Science 338:384-387.
114. Newcomb RD, Campbell PM, Ollis DL, et al. 1997. A single amino acid substitution converts a carboxylesterase to an organophosphorus hydrolase and confers insecticide resistance on a blowfly. Proc Natl Acad Sci USA 94:7464-7468.
115. Noda-Garcia L, Barona-Gomez F. 2013. Enzyme evolution beyond gene duplication: a model for incorporating horizontal gene transfer. Mob Genet Elements 3:e26439.
116. Noor S, Taylor MC, Russell RJ, et al. 2012. Intramolecular epistasis and the evolution of a new enzymatic function. PLoS ONE 7:e39822.
117. Novais A, Comas I, Baquero F, et al. 2010. Evolutionary trajectories of beta-lactamase CTX-M-1 cluster enzymes: predicting antibiotic resistance. PLoS Pathog 6:e1000735.
118. Ortlund EA, Bridgham JT, Redinbo MR, Thornton JW. 2007. Crystal structure of an ancient protein: evolution by conformational epistasis. Science 317:1544-1548.
119. Ostermeier M, Nixon AE, Benkovic SJ. 1999. Incremental truncation as a strategy in the engineering of novel biocatalysts. Bioorg Med Chem 7:2139-2144.
120. Papp B, Notebaart RA, Pal C. 2011. Systems-biology approaches for predicting genomic evolution. Nat Rev Genet 12:591-602.
121. Park HS, Nam SH, Lee JK, et al. 2006. Design and evolution of new catalytic activity with an existing protein scaffold. Science 311:535-538.
122. Patrick WM, Matsumura I. 2008. A study in molecular contingency: glutamine phosphoribosylpyrophosphate amidotransferase is a promiscuous and evolvable phosphoribosylanthranilate isomerase. J Mol Biol 377:323-336.
123. Peisajovich SG, Tawfik DS. 2007. Protein engineers turned evolutionists. Nat Methods 4:991-994.
124. Perfeito L, Ghozzi S, Berg J, Schnetz K, Lassig M. 2011. Nonlinear fitness landscape of a molecular pathway. PLoS Genet 7:e1002160.
125. Phillips PC. 2008. Epistasis-the essential role of gene interactions in the structure and evolution of genetic systems. Nat Rev Genet 9:855-867.
126. Poelwijk FJ, Kiviet DJ, Weinreich DM, Tans SJ. 2007. Empirical fitness landscapes reveal accessible evolutionary paths. Nature 445:383-386.
127. Qasim MA, Lu W, Lu SM, et al. 2003. Testing of the additivity-based protein sequence to reactivity algorithm. Biochemistry 42:6460-6466.
128. Ramos JL, Gonzalez-Perez MM, Caballero A, van Dillewijn P. 2005. Bioremediation of polynitrated aromatic compounds: plants and microbes put up a fight. Curr Opin Biotechnol 16:275-281.
129. Rockah-Shmuel L, Tawfik DS. 2012. Evolutionary transitions to new DNA methyltransferases through target site expansion and shrinkage. Nucleic Acids Res 40:11627-11637.
130. Romero PA, Arnold FH. 2009. Exploring protein fitness landscapes by directed evolution. Nat Rev Mol Cell Biol 10:866-876.
131. Roodveldt C, Aharoni A, Tawfik DS. 2005. Directed evolution of proteins for heterologous expression and stability. Curr Opin Struct Biol 15:50-56.
132. Rothlisberger D, Khersonsky O, Wollacott AM, et al. 2008. Kemp elimination catalysts by computational enzyme design. Nature 453:190-195.
133. Salverda ML, De Visser JA, Barlow M. 2010. Natural evolution of TEM-1 beta-lactamase: experimental reconstruction and clinical relevance. FEMS Microbiol Rev 34:1015-1036.
134. Salverda ML, Dellus E, Gorter FA, et al. 2011. Initial mutations direct alternative pathways of protein evolution. PLoS Genet 7:e1001321.
135. Sanchez-Ruiz JM. 2010. Protein kinetic stability. Biophys Chem 148:1-15.
136. Sanjuan R, Elena SF. 2006. Epistasis correlates to genomic complexity. Proc Natl Acad Sci USA 103:14402-14405.
137. Savile CK, Janey JM, Mundorff EC, et al. 2010. Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329:305-309.
138. Schenk MF, Szendro IG, Krug J, de Visser JA. 2012. Quantifying the adaptive potential of an antibiotic resistance enzyme. PLoS Genet 8:e1002783.
139. Schild SE, Buskirk SJ, Frick LM, Cupps RE. 1991. Radiotherapy for large symptomatic hemangiomas. Int J Radiat Oncol Biol Phys 21:729-735.
140. Segre D, Deluna A, Church GM, Kishony R. 2005. Modular epistasis in yeast metabolism. Nat Genet 37:77-83.
141. Seibert CM, Raushel FM. 2005. Structural and catalytic diversity within the amidohydrolase superfamily. Biochemistry 44:6383-6391.
142. Sieber V, Martinez CA, Arnold FH. 2001. Libraries of hybrid proteins from distantly related sequences. Nat Biotechnol 19:456-460.
143. Siegel JB, Zanghellini A, Lovick HM, et al. 2010. Computational design of an enzyme catalyst for a stereoselective bimolecular Diels-Alder reaction. Science 329:309-313.
144. Smith JM. 1970. Natural selection and the concept of a protein space. Nature 225:563-564.
145. Socha RD, Tokuriki N. 2013. Modulating protein stability-directed evolution strategies for improved protein function. FEBS J 280:5582-5595.
146. Soo VW, Hanson-Manful P, Patrick WM. 2011. Artificial gene amplification reveals an abundance of promiscuous resistance determinants in Escherichia coli. Proc Natl Acad Sci USA 108:1484-1489.
147. Soskine M, Tawfik DS. 2010. Mutational effects and the evolution of new protein functions. Nat Rev Genet 11:572-582.
148. Stebbins J. 1944. The law of diminishing returns. Science 99:267-271.
149. Sun S, Zhang W, Mannervik B, Andersson DI. 2013. Evolution of broad spectrum beta-lactam resistance in an engineered metallo-beta-lactamase. J Biol Chem 288:2314-2324.
150. Taylor JS, Raes J. 2004. Duplication and divergence: the evolution of new genes and old ideas. Annu Rev Genet 38:615-643.
151. Tokuriki N, Tawfik DS. 2009a. Protein dynamism and evolvability. Science 324:203-207.
152. Tokuriki N, Tawfik DS. 2009b. Stability effects of mutations and protein evolvability. Curr Opin Struct Biol 19:596-604.
153. Tokuriki N, Stricher F, Schymkowitz J, Serrano L, Tawfik DS. 2007. The stability effects of protein mutations appear to be universally distributed. J Mol Biol 369:1318-1332.
154. Tokuriki N, Stricher F, Serrano L, Tawfik DS. 2008. How protein stability and new functions trade off. PLoS Comput Biol 4:e1000002.
155. Tokuriki N, Jackson CJ, Afriat-Jurnou L, et al. 2012. Diminishing returns and tradeoffs constrain the laboratory optimization of an enzyme. Nat Commun 3:1257.
156. Tomatis PE, Fabiane SM, Simona F, et al. 2008. Adaptive protein evolution grants organismal fitness by improving catalysis and flexibility. Proc Natl Acad Sci USA 105:20605-20610.
157. Toprak E, Veres A, Michel JB, et al. 2011. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat Genet 44:101-105.
158. Tracewell CA, Arnold FH. 2009. Directed enzyme evolution: climbing fitness peaks one amino acid at a time. Curr Opin Chem Biol 13:3-9.
159. Traxlmayr MW, Obinger C. 2012. Directed evolution of proteins for increased stability and expression using yeast display. Arch Biochem Biophys 526:174-180.
160. van Loo B, Jonas S, Babtie AC, et al. 2010. An efficient, multiply promiscuous hydrolase in the alkaline phosphatase superfamily. Proc Natl Acad Sci USA 107:2740-2745.
161. Varadarajan N, Gam J, Olsen MJ, Georgiou G, Iverson BL. 2005. Engineering of protease variants exhibiting high catalytic activity and exquisite substrate selectivity. Proc Natl Acad Sci USA 102:6855-6860.
162. Vick JE, Gerlt JA. 2007. Evolutionary potential of (beta/alpha)8-barrels: stepwise evolution of a "new" reaction in the enolase superfamily. Biochemistry 46:14589-14597.
163. Voordeckers K, Brown CA, Vanneste K, et al. 2012. Reconstruction of ancestral metabolic enzymes reveals molecular mechanisms underlying evolutionary innovation through gene duplication. PLoS Biol 10:e1001446.
164. Wackett LP. 2009. Questioning our perceptions about evolution of biodegradative enzymes. Curr Opin Microbiol 12:244-251.
165. Wagner A. 2008. Neutralism and selectionism: a network-based reconciliation. Nat Rev Genet 9:965-974.
166. Walkiewicz K, Benitez Cardenas AS, Sun C, et al. 2012. Small changes in enzyme function can lead to surprisingly large fitness effects during adaptive evolution of antibiotic resistance. Proc Natl Acad Sci USA 109:21408-21413.
167. Wang X, Minasov G, Shoichet BK. 2002. Evolution of an antibiotic resistance enzyme constrained by stability and activity trade-offs. J Mol Biol 320:85-95.
168. Weinreich DM, Watson RA, Chao L. 2005. Perspective: sign epistasis and genetic constraint on evolutionary trajectories. Evolution 59:1165-1174.
169. Weinreich DM, Delaney NF, Depristo MA, Hartl DL. 2006. Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312:111-114.
170. Wells JA. 1990. Additivity of mutational effects in proteins. Biochemistry 29:8509-8517.
171. Weng JK. 2013. The evolutionary paths towards complexity: a metabolic perspective. New Phytol 201:1141-1149.
172. Weng JK, Philippe RN, Noel JP. 2012. The rise of chemodiversity in plants. Science 336:1667-1670.
173. Wright XS. 1932. The roles of mutation, inbreeding, crossbreeding and selection in evolution. Proceedings of The Sixth International Congress of Genetics 1: 356-366.
174. Wyganowski KT, Kaltenbach M, Tokuriki N. 2013. GroEL/ES buffering and compensatory mutations promote protein evolution by stabilizing folding intermediates. J Mol Biol 425:3403-3414.
175. Zhao H, Giver L, Shao Z, Affholter JA, Arnold FH. 1998. Molecular evolution by staggered extension process (StEP) in vitro recombination. Nat Biotechnol 16:258-261.