Why synonymous mutations are not always silent: Modeling shows how genetic changes that don’t lead to changes in protein sequence can still alter protein function

New modeling shows how synonymous mutations — those that change the DNA sequence of a gene but not the sequence of the encoded protein — can still impact protein production and function.

A team of researchers led by Penn State chemists modeled how genetic changes that alter the speed of protein synthesis, but not the sequence of amino acids that comprise the protein, can lead to misfolding that changes the protein’s activity level, and then corroborated their models experimentally.

The results demonstrate the importance of kinetics — the rate of protein synthesis — in addition to sequence for determining protein structure and function and could have implications in fields such as biopharmaceutics for fine tuning the activity of synthesized proteins.

Proteins are composed of long strings of amino acids that then fold up into three-dimensional functional structures. Each amino acid is encoded by a triplet of letters in the DNA alphabet of A, T, C and G called a codon, but there is redundancy built in to the system such that more than one codon can correspond to the same amino acid.

Therefore, a mutation that changes the DNA sequence of a gene won’t necessarily change the sequence of the encoded protein if the mutation results in a “synonymous codon.” To make a protein, DNA in the nucleus of a cell is first transcribed into a messenger RNA (mRNA). The mRNA is then transported out of the nucleus where it is translated into a nascent protein by a cellular organelle called a ribosome. After translation the protein is folded into its final functional form.

“We used to use ‘synonymous’ and ‘silent’ interchangeably to describe mutations that don’t change a protein’s sequence because it was thought that they wouldn’t alter the function of the protein,” said Ed O’Brien, professor of chemistry and a member of the Institute for Computational and Data Sciences at Penn State, and one of the leaders of the research team. “But, we’ve known for some time now that not all synonymous mutations are silent. Over two decades ago, it was shown that synonymous mutations could reduce the activity of proteins, but it was still unknown what was happening at the molecular level to cause this change.”

The research team used a multi-scale modeling approach, using theory and computation to simulate what is happening at the molecular level during protein synthesis, to predict changes in protein structure that could result from synonymous mutations and therefore alter the protein’s activity. A paper describing the research appears Dec. 5 in the journal Nature Chemistry.

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