ACS Chemical Biology (41) Yokoyama, S., Nishimura, S. (1995) Modiﬁed nucleosides and codon recognition, in tRNA: Structure, Biosynthesis, and Function (Soll, D., and RajBhandary, U. L., Eds.), pp 207−223, ASM Press, Washington, DC. (42) Schrader, J. M., Chapman, S. J., and Uhlenbeck, O. C. (2011) Tuning the aﬃnity of aminoacyl-tRNA to elongation factor Tu for optimal decoding. Proc. Natl. Acad. Sci. U.S. . 108, 5215−5220. (43) Ledoux, S., and Uhlenbeck, O. C. (2008) Diﬀerent aa-tRNAs are selected uniformly on the ribosome. Mol. Cell 31, 114−123. (44) Kato, J., and Hashimoto, M. (2007) Construction of consecutive deletions of the Escherichia coli chromosome. Mol. Syst. Biol. 3, 132. (45) Inagaki, Y., and Ford Doolittle, W. (2000) Evolution of the eukaryotic translation termination system: origins of release factors. Mol. Biol. Evol. 17, 882−889. (46) Moreira, D., Kervestin, S., Jean-Jean, O., and Philippe, H. (2002) Evolution of eukaryotic translation elongation and termination factors: variations of evolutionary rate and genetic code deviations. Mol. Biol. Evol. 19, 189−200. (47) Johnson, D. B., and Wang, L. (2010) Imprints of the genetic code in the ribosome. Proc. Natl. Acad. Sci. U.S.A. 107, 8298−8303. (48) Crick, F. H. (1968) The origin of the genetic code. J. Mol. Biol. 38, 367−379. (49) Trifonov, E. N. (2004) The triplet code from ﬁrst principles. J. Biomol. Struct. Dyn. 22, 1−11. Letters 1344 dx.doi.org/10.1021/cb300229q | ACS Chem. Biol. 2012, 7, 1337−1344