Molecular Biology survival guide for Chemists — III: Codons, synonymous and not

Chemistry wouldn’t be what it is without quantum mechanics.  No, I’m not talking about solving the Schrodinger equation, or the approximations we must use for any minimally complicated molecule.  The fact that the energy levels of each element are quantized, means that each element acts exactly the same way, so the carbon atom at the edge of the universe has exactly the  same energy levels as the carbon atoms in the 10 billion bacteria in each gram of the stuff sitting in your colon.

What about codons?

Each of the amino acids found in proteins is one of 20 possibilities, each position of DNA (a nucleotide) is one of four possibilities, so 2 consecutive nucleotides aren’t enough (16 possibilities) while 3 are too many (44 too many in fact). Each of the 64 possible combinations of 4 nucleotides taken 3 at a time is called a codon.  3 of the 64 don’t code for an amino acid at all — they are (inappropriately) called nonsense codons.  Their function, however, is vital.  They tell the cellular machinery making a protein (e.g. the ribosome) to stop adding amino acids to the chain.  41 extra codons is a lot of redundancy, so that some amino acids (leucine for example) have 6 different codons which code for them — the 6 are called synonymous codons. Other amino acids (methionine) have just one codon for them.  Each choice of 3 nucleotides (a codon) codes for one and only one amino acid.

Codons are therefore either synonymous or nonsynonymous.  So changing one nucleotide for another in a codon may lead to a change in the amino acid it was coding for, or it may not.  If it doesn’t, the thinking until a few years ago that natural selection shouldn’t care as the amino acid sequence of the protein remained unchanged (and proteins were thought to be the only thing DNA codes for back then).  Since changing one synonymous codon to another (say by mutation) doesn’t change the protein made these were called neutral mutations.

Much evolutionary hay was made using these concepts.  People attempted to measure the rate of natural selection acting on proteins using synonymous and nonsynonymous codons in the same protein in different organisms (hemoglobin for example).  Positive selection is measured as the rate of nonsynonymous nucleotide substitution (Ka) per nonsynonymous site, relative to the underlying ‘neutral mutation’ given by the rate of synonymous substitution per synonymous site (Ks).  Usually Ka is much less than Ks (as most new mutations aren’t helpful or are actually harmful — this is negative selection).  Positive selection is implied by a Ka/Ks ratio greater than 1.    However, strictly by chance  the ratio of nonsynonymous (Ka) to synonymous (Ks) amino acid substitutions is 2:1.

However, there are several very well documented examples of synonymous codons acting very differently.  That’s for the next post.

One last technical point.  Each of the 44 possible codons has a transfer RNA (tRNA) associated with it, along with an enzyme (tRNA synthase, aka tRNA synthetase) which takes one specific amino acid, and plunks it onto the tRNA specific for  a particular codon.  The possibilities for error are enormous.  Just look how close chemically and structurally serine and threonine are, or phenylalanine and tyrosine, or glutamic and aspartic acid.  tRNA synthases containing proofreading capacity to make sure that the right amino acid gets linked to the right tRNA.  The error rate is impressively low — mistakes in selecting the amino acid occurs every 1/10,000 – 1/100,000, and a mistake in the selection of the tRNA occurs every 1/1,000,000 [ Cell vol. 103 pp. 877 – 894 ’00 ].  Remember the synthetase has to grab the correct tRNA and the correct amino acid and then stitch them together.   It is thought that the error rate between synthase and tRNA is so low, because both the enzyme and the tRNA  molecules are large, allowing a large number of contacts to be formed (correctly) between the two of them, providing a lot of ways to detect a mismatch.

Well, that’s the background.  Now to see what nature (or something) has made of all this.

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