Nobel Prize in chemistry – comment by prof. Łukasz Opaliński
Nobel Prize in chemistry – comment by our expert from UWr Faculty of Biotechnology
What is the significance of the findings of three researchers David Baker, Demiss Hassabis and John M. Jumper? Prof. Łukasz Opaliński, winner of the NCN 2023 Award, the most prestigious award for young scientists working in Poland, talks about this year’s Nobel Prize in Chemistry.
It is widely believed that it is impossible for the living world to exist without proteins. Proteins, by catalyzing thousands of chemical reactions, enable very rapid (even on the microsecond scale) complex cascades of metabolic changes to take place in cells that would take millions of years to occur without the help of proteins. Proteins are the main effector macromolecules of the living world, among other things, enabling the cell to form a complex architecture, ensuring cell movement, transmitting signals, duplicating cells or reading genetic information.
So it is not surprising that most human diseases, including cancer, neurodegenerative, autoimmune or metabolic diseases are associated with malfunctioning proteins.
The amazing medical advances of the last fifty years, provided by developments in medical biotechnology and chemistry, have made it possible to treat many previously incurable diseases caused by malfunctioning proteins, but we are still faced with the urgent need to inhibit or repair cellular processes caused by malfunctioning proteins. There are also tremendous opportunities to use natural proteins and their semi-synthetic or synthetic variants in biomedicine (e.g., as biological drugs, drug carriers, biosensors).
Proteins are made up of 20 different amino acids, which are arranged in a protein-specific order (protein sequence) and are linked together to form a “chain” (the protein’s primary structure). Thanks to the specific properties of amino acids and a great many interactions between atoms, the “chain” of amino acids coils into certain smaller structural modules (secondary structures), and then forms the final three-dimensional structure of the protein (tertiary structure). Some proteins are active only when several protein molecules interact to form an oligomer (quaternary structure). The sequence information, and therefore the final structure of the protein, is encoded in our DNA, where we can find about 25,000 protein-coding genes. However, the final number of proteins in human cells is greater (about 100,000) than the number of protein-coding genes, due to the multilevel regulation of gene expression and modification of nascent proteins. Since the living world is not just humans, it is estimated that there may be hundreds of millions of different proteins in the environment around us.
Crucially, what function a protein has in a cell depends on its spatial structure. In 1958, we learned the first atomic structure of the myoglobin protein (John Kendrew, Max Perutz; Nobel Prize in Chemistry, 1962), and since then countless researchers have conducted interdisciplinary research on the relationship between protein structure and function, leading to the decipherment of the molecular architecture of a great many proteins and understanding, for example, the molecular basis of a number of diseases. However, learning the structure of even a single protein is often a very difficult, time-consuming and expensive task, and in many cases even impossible until now.
For about 50 years, there was a concept that assumed that the three-dimensional structure of a protein could be predicted solely on the basis of its amino acid sequence. Since the process of forming the final structure by an amino acid chain requires a great variety of interactions between atoms, this task was very difficult and required extremely broad chemical and biochemical knowledge, resulting in quite limited progress in this field.
In 2020, Demis Hassabis (University College London, UK) and John M. Jumper (University of Chicago, USA) released AlphaFold2, an artificial intelligence-based tool they developed to predict the 3D structure of proteins. With its help, more than two million scientists from nearly 200 different countries have succeeded in predicting the structure of almost all proteins known to us so far (about 200,000,000). It is worth noting, however, that experimental confirmation will be required in the future for many of these theoretical structure models. Hassabis and Jumber were awarded the Nobel Prize in Chemistry this year for this discovery.
The significance of this discovery is extremely high, both in terms of fundamentals (it will contribute to the understanding of the mechanisms that govern the living world, the molecular basis of infections and diseases, the nano-architecture of cells) and applications (designing new proteins of biomedical importance, drugs, enzymes for industry and healthcare).
The second part of this year’s Nobel Prize in Chemistry is also inextricably linked to learning about protein structure.
As mentioned above, learning how an amino acid chain (sometimes made up of more than 1,000 repeats of 20 amino acids in different order) forms the three-dimensional structure of a protein is an extremely complicated process, and a thorough understanding of the structure and function of proteins found in nature, despite the invaluable help of AlphaFold2, is still ahead of us.
David Baker of the University of Washington, USA, went one step further and decided to use his vast knowledge of the protein structure formation process to design macromolecules with the desired architecture, but fully artificial, absent in nature. The concept of de novo protein design had existed in the scientific field for many years, but it was David Baker who in 2003 achieved spectacular success by presenting the first protein with his planned structure, thus proving that de novo protein design is possible. Then, for more than 20 consecutive years, David Baker and his team solidified their discovery, developing a whole repertoire of proteins with extremely interesting properties that can serve as drugs, vaccines, or biosensors, expanding beyond natural possibilities, almost to infinity, the potential of proteins in biomedicine.
Interestingly, researchers at the UWr Faculty of Biotechnology are focusing their research on topics that coincide with this year’s Nobel Prizes and are successfully designing semi-synthetic proteins with biomedical potential.
Prof. dr. hab. Łukasz Opaliński, winner of the NCN 2023 Award
