The Kinetic Basis of the Genetic Code

The origin of the genetic code is an enigma, requiring explanations for the emergence of degeneracy, the organizational structure of the code, and the correspondence between codons and amino acids. Here, we use a recently-proposed asymmetric cooperativity model to show that these features arise from asymmetric cooperativity in codon anticodon association process. We first provide mechanistic and evolutionary accounts of wobble-base-pair degeneracy, without providing any preferential treatment to the third position. The model, with four tunable parameters, reproduces the organizational structure of the genetic code, and provides theoretical codon-anticodon association times. Although ribosomal kinetic data are not used in parameter estimation, these theoretical association times correlate with experimentally determined ribosomal residence times (r = 0.73), providing an independent empirical correspondence. The resulting timescales, extending over four decades, also exhibit correlations with diverse physicochemical properties of amino acids, at multiple timescales, motivating a nonequilibrium picture in which energy released during codon anticodon association is transferred to its cognate amino acid to be dissipated into water. Finally, without incorporating information about aminoacyl-tRNA synthetases or further parameter adjustment, the model recovers the fundamental division of amino acids associated with the two aminoacyl-tRNA synthetase classes, with a combined segregation score of 0.92 (p ∼10−8). Together, these results suggest that wobble degeneracy, genetic-code organization, translation kinetics, amino-acid physicochemistry, and the two-class organization of aminoacyl-tRNA synthetases may reflect a common underlying kinetic constraint. We propose that non-equilibrium, asymmetrically cooperative kinetics, that possibly underlie DNA/RNA replication process, also provided a physical basis upon which the genetic code and its subsequent translation machinery evolved.