Earlier this year, Professor Nicolas Doucet and his team at the National Institute for Scientific Research (INRS) made a breakthrough in the evolutionary conservation of molecular dynamics in enzymes. Their work published in the journal buildingindicates potential applications in health, including the development of new drugs to treat serious diseases such as cancer or to counteract antibiotic resistance.
As a researcher specializing in protein dynamics, Professor Doucet is fascinated by things that are not visible to the naked eye, but are full of secrets and essential to all forms of life. It studies proteins and enzymes, and the poorly understood connections between their structure, function, and movement at the atomic level.
In order to better visualize unexplored avenues of research, an enzyme engineering specialist begins by examining problems from a conceptual point of view.
“A little imagination may be all it takes to conceive of multiple avenues of research in this small world of which we still know relatively little, but whose scientific process is so delicate,” said Professor Doucet, researcher at Armand-Frappier Santé Biotechnologie Research. Center and Scientific Co-Chair of the NMR Spectroscopy Laboratory at the National Institute of Statistics.
Towards a better understanding of the function of macromolecules
As part of this study, Professor Doucet’s team investigated an issue that experts in the field considered fundamental: If a particular protein or enzyme relies on conformational change of its three-dimensional structure to perform its biological function in humans, then homologous enzymes do in others. Vertebrates or other organisms also depend on the same conformational changes? In other words, if certain movements are essential to the biological function of proteins and enzymes, are these changes in conformation selected for and conserved as a molecular evolutionary mechanism throughout life?
Despite our limited understanding of how these large molecules essential to life function on Earth, the team attempted to answer this question.
Advances in biochemical and biophysical technology in recent decades have made it easier to observe the molecular structures of proteins and enzymes.
“We studied different enzymes from the same family to analyze several proteins that exhibit the same biological function. We compared their movements at the atomic scale to reveal whether they were conserved throughout evolution. Despite the general similarities between species, we were surprised to discover that, in contrast to However, the movements are disparate,” explained lead author of the study, David Bernard, an INRS graduate who was a PhD student in Professor Doucet’s lab at the time. He now works as a researcher at NMX.
Molecular motions are of great importance
The molecular function of a protein or enzyme depends not only on its amino acid sequence, but also on its three-dimensional (3D) structure. In recent years, scientists have discovered that protein dynamics is closely related to the biological activity of certain enzymes and proteins.
If this is the case for a particular enzyme, what about the preservation of these movements from an evolutionary standpoint? In other words, are specific atomic motions in the enzyme family always present and similarly conserved to maintain biological function?
This implies that atomic scale movements within proteins are an important determinant of the selective pressure that is experienced to maintain biological function, similar to the preservation of amino acid sequence or protein structure.
In this article, Professor Doucet’s team and their American collaborators present a molecular and dynamic analysis of several ribonucleases, enzymes known as RNases that catalyze the degradation of RNA into smaller elements. RNases have been selected from a handful of vertebrate species, including primates and humans, on the basis of structural and functional symmetry.
This study, which builds upon* research previously published by the team, convincingly demonstrates that RNases that maintain specific biological functions in different species also maintain a very similar dynamic profile among themselves. In contrast, structurally similar RNases with distinct biological function show a unique dynamic profile, strongly suggesting that conservation of dynamics is related to biological function in these biocatalysts.
Elucidation of the basic motions of protein or enzyme function therefore holds promise for exploiting its therapeutic potential. This could provide a potential target for controlling protein and enzyme functions in the cell, an area known as allosteric modification or inhibition.
For example, successfully inhibiting an enzyme by binding a drug to its active (or orthogonal) site while targeting an allosteric site on the surface of a protein might kill two birds with one stone. The idea here is to inhibit the enzyme’s active site while simultaneously disrupting its molecular dynamics by targeting the allosteric site. This inhibitory action would also greatly reduce the development of antibiotic resistance.
Drug resistance is a global health issue. In recent years, antibiotic resistance in the fight against bacteria in humans and farm animals has been one of the most compelling and widespread examples.
In conclusion, because specific molecular motions can be observed uniquely in some families of enzymes, this will allow researchers to achieve a remarkable degree of selectivity in developing unique allosteric inhibitors – all without affecting structurally or functionally homologous enzymes.