Introduction

There are more than one codon for one amino acid. This is called degeneracy of genetic code. To explain the possible cause of degeneracy of codons, in 1966, Francis Crick proposed “the Wobble hypothesis”.

According to The Wobble Hypothesis, only the first two bases of the codon have a precise pairing with the bases of the anticodon of tRNA, while the pairing between the third bases of codon and anticodon may Wobble (wobble means to sway or move unsteadily).

The phenomenon permits a single tRNA to recognize more than one codon. Therefore, although there are 61 codons for amino acids, the number of tRNA is far less (around 40) which is due to wobbling.

The Wobble Hypothesis is a concept in molecular biology that explains how the genetic code is interpreted during protein synthesis, specifically in the context of codon-anticodon interactions in the ribosome during translation. It was first proposed by Francis Crick in 1966.

In the genetic code, a sequence of three nucleotides in a messenger RNA (mRNA) molecule is known as a codon. Each codon codes for a specific amino acid, the building blocks of proteins. Transfer RNA (tRNA) molecules are responsible for carrying the corresponding amino acids to the ribosome during translation.

The Wobble Hypothesis addresses the phenomenon that there are more codons (64 possible codons) than there are tRNA molecules carrying amino acids (around 20 different tRNA molecules). This raises the question of how the genetic code is read accurately, considering that some tRNA molecules must be able to recognize and bind to multiple different codons. The Wobble Hypothesis explains this by introducing a degree of flexibility or "wobble" in the base-pairing rules between the third position of the codon (the 5' end) and the first position of the anticodon (the 3' end) of the tRNA.

The Wobble Hypothesis Statement

The wobble hypothesis states that the base at 5′ end of the anticodon is not spatially confined as the other two bases allowing it to form hydrogen bonds with any of several bases located at the 3′ end of a codon.

This leads to the following conclusions:

• The first two bases of the codon make normal (canonical) H-bond pairs with the 2nd and 3rd bases of the anticodon.
• At the remaining position, less stringent rules apply and non-canonical pairing may occur. The wobble hypothesis thus proposes a more flexible set of base-pairing rules at the third position of the codon.
• The relaxed base-pairing requirement, or “wobble,” allows the anticodon of a single form of tRNA to pair with more than one triplet in mRNA.
• The rules: first base U can recognize A or G, first base G can recognize U or C, and first base I can recognize U, C or A.
• Standard Base Pairing: In the first and second positions of the codon-anticodon interaction, standard Watson-Crick base pairing occurs. For example, adenine (A) in the mRNA codon pairs with uracil (U) in the tRNA anticodon via a complementary base pairing, and guanine (G) in the mRNA codon pairs with cytosine (C) in the tRNA anticodon.
• Wobble Base Pairing: In the third position of the codon (5' end) and the first position of the anticodon (3' end), the base pairing rules are less stringent. This allows for some degree of flexibility in the pairing. For example:
• Codons ending in adenine (A) can pair with tRNAs carrying uracil (U) or adenine (A) at the first anticodon position.
• Codons ending in cytosine (C) can pair with tRNAs carrying guanine (G) or uracil (U) at the first anticodon position.
• Codons ending in guanine (G) can pair with tRNAs carrying cytosine (C) at the first anticodon position.
• Codons ending in uracil (U) can pair with tRNAs carrying adenine (A) or guanine (G) at the first anticodon position.

Crick’s hypothesis hence predicts that the initial two ribonucleotides of triplet codes are often more critical than the third member in attracting the correct tRNA.

Wobble base pairs

• A wobble base pair is a pairing between two nucleotides in RNA molecules that does not follow Watson-Crick base pair rules.
• The four main wobble base pairs are guanine-uracil (G-U), hypoxanthine-uracil (I-U), hypoxanthine-adenine (I-A), and hypoxanthine-cytosine (I-C).
• In order to maintain consistency of nucleic acid nomenclature, “I” is used for hypoxanthine because hypoxanthine is the nucleobase of inosine.
• Inosine displays the true qualities of wobble, in that if that is the first nucleotide in the anticodon then any of three bases in the original codon can be matched with the tRNA.

Top of Form

Bottom of Form

Significance of the Wobble Hypothesis

• Our bodies have a limited amount of tRNAs, and wobble allows for broad specificity.
• Wobble base pairs have been shown to facilitate many biological functions, most clearly proven in the bacterium Escherichia coli.
• The thermodynamic stability of a wobble base pair is comparable to that of a Watson-Crick base pair.
• Wobble base pairs are fundamental in RNA secondary structure and are critical for the proper translation of the genetic code.
• Wobbling allows faster dissociation of tRNA from mRNA and also protein synthesis.
• The existence of wobble minimizes the damage that can be caused by a misreading of the code; for example, if the Leu codon CUU were misread CUC or CUA or CUG during transcription of mRNA, the codon would still be translated as Leu during protein synthesis.

This wobble pairing allows a single tRNA molecule to recognize multiple codons with similar sequences in the third position, reducing the requirement for a separate tRNA molecule for each codon. It provides some redundancy and flexibility in the genetic code, ensuring that the correct amino acid is incorporated into the growing polypeptide chain during translation.

The Wobble Hypothesis has since been supported by experimental evidence and is a fundamental concept in molecular biology, explaining how the genetic code is efficiently and accurately translated into proteins despite the redundancy in codon-anticodon interactions.