Do proteins remember?

A study integrating biological insights and new computational tools has discovered new associations between genetic coding and protein structure that could potentially change the way we think about protein production in the ribosome, the “protein assembly line”. ” of the cell. The research, led by Professor Alex Bronstein, Dr. Ailie Marx and Ph.D. student Aviv Rosenberg, has been published in Nature Communication.

The proteins, the complex molecules which play a critical role in virtually all biological mechanisms, are produced by ribosomes in a process called translation. The ribosome decodes incoming “genetic instructions” to synthesize chains of amino acids – the building blocks of proteins. When amino acids are sequentially linked together in a long chain, they fold into a unique three-dimensional structure that gives the protein its biological properties and functionality. Translation errors can lead to poor folding and subsequent physiological disorders, whether mild or major.

Protein production instructions are passed to the ribosome in the form of codons, sequences of three “letters” of the genetic code of nucleotides, which specify the identity and order of amino acids to be added by the ribosome to the protein chain. For example, the UUU codon signals the addition of the amino acid phenylalanine, while the UAC codon requests the addition of tyrosine. In this way, the codon sequence codes for the unique amino acid sequence characteristic of each protein. This mapping of genetic codons to amino acids used in translation is common to all living creatures on the planet and is believed to be a primitive mechanism.

As if all of this weren’t complicated enough, it’s important to point out that there are 61 codons that are decoded into just 20 amino acids. In other words, all but two amino acids are encoded by several codons.

This is where current research comes into play. Based on experiments in the 1960s and 1970s, accepted dogma states that proteins carry no “memory” of the specific codon from which each amino acid was translated as long as the identity of the amino acid remains. unchanged. These early protein folding experiments used chemical denaturants to unfold fully formed proteins, then demonstrated that upon removal of these chemicals, the protein chain could spontaneously fold back to its original structure and function. These experiments suggested that only the amino acid sequence, not the specific codon sequence, determines the structure of a protein. In view of this dogma, mutations that alter the genetic coding without altering the amino acid are widely referred to as “silent” and considered inconsequential to protein structure and function.

The Technion research team found an association between codon identity and the local structure of the translated protein, suggesting that this may not be the general case and that proteins can indeed remember” the specific instructions from which they were synthesized. The research team analyzed thousands of three-dimensional protein structures using dedicated tools they developed, which integrate advanced computational methods, machine learning and statistics. In this way, they accurately compared the distributions of the angles formed in these structures under different synonymous genetic codes. Their results show that for certain codons, there is a significant statistical dependence between the identity of the codon and the local structure of the protein, at the position of the amino acid encoded by this codon.

The researchers point out that the results still do not shed light on the direction of the causal relationship, which means that it is not yet possible to say whether a change in the genetic coding can lead to a change in the protein structure or whether structural changes may result in different coding, for example through evolutionary processes. This question is the basis of a subsequent research study currently being conducted by the group. According to Dr. Marx, a biologist by training and education, “If we discover in further research that the codon does indeed have a causal effect on protein folding, it will probably have a huge impact on our understanding of protein foldingas well as future applications, such as the engineering of new proteins.”

Dr. Marx points out that the discovery presented in the article would not have been possible without the computing and analytical skills of Professor Bronstein. “This research is truly interdisciplinary, because biology alone cannot cope with such large amounts of data without the help of data science, and computer scientists themselves cannot perform such research, because they lack familiarity with the complex biological processes that are being probed. Therefore, our research highlights the tremendous benefit of interdisciplinary research that integrates skills from different fields to create a whole greater than the sum of its parts.”