From the Wobble to Reliable Hypothesis

A simple explanation for the symmetry and degeneracy of the genetic code has been suggested. An alternative to the wobble hypothesis has been proposed. This hypothesis offers explanations for: i) the difference between thymine and uracil, ii) encoding of tryptophan by only one codon, iii) why E. coli have no inosine in isoleucine tRNA, but isoleucine is encoded by three codons. The facts revealed in this study offer a new insight into physical mechanisms of the functioning of the genetic code. The wobble hypothesis, which was first proposed more than 40 years ago [1], can explain two events: 1) formation of the uracil-guanine pair as a result of codon-anticodon interaction in the third position and 2) encoding of isoleucine by three codons (for the universal genetic code). This hypothesis is based on two statements: in the third position of the codon nucleotides can ―wobble‖, and inosine can form pairs with uracil, cytosine, and adenine. Neither of these statements is necessary for explaining the abovementioned events, and the wobble hypothesis is just wrong. Once we admit this, we can get a better insight into the structure and functioning of the genetic code. Crick's hypothesis completely ignores two chemical factors. The first is the stacking between two neighboring nucleotides, and the second is the ability of uracil to be present in the enol form. What makes the uracil-guanine pair possible? Uracil can exist either in the enol form or in the keto form. Uracil in the enol form can make two and even three hydrogen bonds with guanine, while uracil in the keto form would be able to make only one hydrogen bond. One can say that the enol form of uracil is stabilized by its interaction with the complementary guanine. The molecular basis of the wobble hypothesis has been criticized by other researchers [2, 3], but I'd like to add a few comments. Watson first considered nucleotide formulae in the enol form as the more probable, guided by reference books of that time [4]. Fortunately, I can give convincing arguments using commonly available information. Codon-anticodon interaction results in the formation of a short segment of the double helix. In the case of some codons, opposite to uracil in the third position of the codon there is inosine in the anticodon. Crick's wobble hypothesis [1] allows a solution for this pair only by wobbling the third nucleotides of the codon and the …