The Alfred P. Sloan Foundation supports a collaboration involving Brian Kuhlman’s protein design group at UNC, Peter Wills  in the Department of Physics, Centre for Computational Evolution, and Te Ao Marama at the University of Auckland, Mark Ditzler at NASA Ames, and Milena Popovic at Blue Marble Space Institute of Science.

The aminoacyl-tRNA synthetases (aaRS) translate the genetic code by activating specific amino acids and transferring their carboxylate groups to the 3′-terminal adenosine of tRNA.  By selecting exclusive sets of amino acids and symbols (tRNAs) aaRS*tRNA cognate pairs function computationally, as AND gates.

Rodin and Ohno proposed in 1995 that the unusual duality of the two distinct aaRS superfamilies has its roots in an ancestral gene encoding a Class I ancestor on one strand and a Class II ancestor on the complementary strand. We have adduced quite strong evidence from multiple sources that support this hypothesis.

A key bit of evidence comes from the amino acid specificity spectra of the two aaRS we have characterized experimentally in the greatest detail, those for Class I leucyl- and Class II histidyl-tRNA synthetase.

Among other key evidence is a remarkable propagation of the fundamental genetic complementarity into the proteome; the two aaRS classes display an inverse structural complementarity that accounts for differentiation at the secondary structure level of specific recognition of both amino acid and tRNA substrates.

The reverse complementary structures of Class I and II account for their ability to differentiate between both amino acid and tRNA substratesaRS secondary structures

Considerable structural and experimental evidence thus help to define how genetic coding developed its first bit of information, allowing nature to begin specifying binary patterns in coded peptides, necessary and, we believe also sufficient to initiate specification of binary patterns consistent with α-helical (0011110) and β-strand (010101) secondary structures.

We have also shown that excerpted aaRS urzyme sequence alignments have phylogenetic metrics by which they can be differentiated from sequences excerpted from the remaining segments (Carter CW, Popinga A, Bouckaert R, Wills PR. 2022. Multidimensional Phylogenetic Metrics Identify Class I Aminoacyl-tRNA Synthetase Evolutionary Mosaicity and Inter-modular Coupling. International Journal of Molecular Sciences 23: 1520).


These observations furnish a framework from which we hope to reconstruct ancestral amino acid and tRNA sequence probability distributions from which we can construct libraries of plausible aaRS urzymes with different specificity spectra as a means to map out the evolutionary history of the genetic coding table.