The Wobble Theory

Assumption:

Each tRNA, defined by its 3-base anticodon, pairs only with its complementary codon on the mRNA.

Discrepancy:

tRNA^Ala was found to bind to codons `GCA`, `GCC` and `GCU`.

Codon (5'->3') Anticodon (3'->5') GCA CGU GCC CGG GCU CGA

The answer:

The tRNA^Ala anticodon is actually `CGI` which pairs with all three codons.

Experimentally determined codon-anticodon pairing rules:

The first two positions of the mRNA codon observe Watson-Crick base pairing rules (A-U, C-G)
The third position exhibits wobble.
Wobble occurs because the conformation of the tRNA anticodon loop permits flexibility at the first base of the anticodon.

5' anticodon base (tRNA)	3' codon base (mRNA)
`A` (not observed)	`U` (Watson-Crick)
`C`	`G` (Watson-Crick)
`G`	`C` or`U`
`U`	`A` or`G`
`I`	`A` or`C`or`U`

Caveat: Since a single tRNA can respond to more than one codon, one tRNA could respond to codons for two different amino acids! This would lead to an ambiguous code. But since the Genetic Code is unambiguous, certain anticodons are disallowed.

Next: The Dangers of Wobble

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