Proteins are the building blocks, motors and regulators of life. These special macromolecules are composed by the complex folding of amino acids chains, which result from the transcription of DNA and RNA. In theory, understanding the structure of these molecules might seem straightforward: it is simply a folded chain of the 20 relevant amino acids. However, things are not so simple. Proteins do not only present any folded amino acids structure, but they present those structures linked to specific functions. For instance, haemoglobin does not present a random configuration of its amino acids, but a specific folded structure. While in the cell the process of folding takes up only few milliseconds and generally it leads to functional proteins, if the chain of amino acids were to just fold randomly it would take an incredibly long amount of time to find the right functional structure. There are indeed multiple ways in which those amino acids strings could fold, and only some of them are functional. This generated the so-called “problem of protein folding”: how do we move from an amino acids chain to a folded functional protein and how do we unpack a protein to find why it folded in that specific functional way?
These are the questions addressed by the teams of the scientists that got awarded the Nobel Prize in Chemistry 2024. The first half of the prize goes to David Baker and his lab team, who were able to develop computer methods (a program called Rosetta) that could design proteins, either based on known models or by proposing new ones not yet found in nature and display new functions. This research allows to move from the amino acids sequence to the folded structure and back, permitting novel protein design and increasing the applications that engineered proteins can have. The second half of the prize has been given to Demis Hassabis and John Jumper, who worked on the development of the artificial intelligence program AlphaFold2, which is able to predict the final folded structure of almost 200 million known proteins.
But what is so fascinating about predicting the relation between the primary structure of a protein and its globular structure on the one hand and the capacity to design new proteins on the other?
Firstly, the “protein folding problem” has been one of the main problems for contemporary biochemistry and molecular biology, and the research of these labs gave a crucial advantage to dealing with it. In a nutshell, these technologies provide an answer to an important problem regarding the understanding of proteins structure and its complexity. This also brings in a level of fascination related to the application of novel computational technologies, which enables reach new results at a much faster speed and can allow for the discovery of entirely new proteins.
Secondly, answering the protein folding problem is important because the relation between the primary and tertiary/quaternary structure is crucial for proteins’ functionality. A good understanding of these phenomena allows a comprehension not only of proteins structure, but also of proteins function and allows for such functions to be manipulated. By associating the function of the protein to the right level of structure we can predict and design proteins useful for pharmaceutical and vaccine designs and many more research strands.
Thirdly, these discoveries provide insights on many philosophical debates. A better understanding of the relation between structure and function in proteins (or between primary and tertiary structure) has an impact on how we think of the distinction between chemical and biological entities. Often the two are distinguished in terms of the first being characterised structurally and the second being characterised functionally. However, things get more blurred when we consider the fact that proteins can be characterised by both structure and function. It is their tertiary structure that crucially determines the protein functionality and therefore has an impact on multiple features of life. Accordingly, a better understanding and prediction of the structure and function of proteins can allow us to explore whether the dichotomy between life and non-life is as sharp as it seems in light of function characterisation. This also has an impact also on how we think of the domain definition and separation between molecular biology and biochemistry and more generally chemistry and biology themselves. Generally, biochemistry (and chemistry) is seen as the discipline that focuses on chemical structures, chemical reactivity and chemical processes present in biological phenomena. Molecular biology instead can be seen as the discipline that focuses on genes’ expression for biological functionality, evolutionary pressure and selection and the overall role in organisms. For instance, biochemistry might be seen as interested in protein folding and maintenance of proteins structure, while molecular biology might be seen as interested in which genes have been selected for encoding given proteins. However, the results awarded by the Nobel prize deliver a way more unified picture of proteins, whose understanding and design cannot be disentangled from their functionality and the role they play in organisms. This can also illuminate the philosophical debate on the kindhood of proteins. The literature is divided between pluralism (many accounts of kindhood should be used), functionalism (proteins should be characterised in terms of function), reductionism (proteins should be characterised in terms of chemical structure) and dualism (proteins are kinds both chemical and functional). The model and image of proteins which we can infer from the awarded research allow us to see how the characterisation should be unified and comprise both structural and functional features, including the primary structure and the tertiary. These results support an understanding of structure and function as “two sides of the same coin” and that we cannot understand structure without considering function and the opposite.
Selected references
• Åqvist, Johan 2024, “Computational Protein Design and Protein Structure Prediction”, Scientific Background to the Nobel Prize in Chemistry 2024 https://www.nobelprize.org/prizes/literature/2024/summary/
• Bellazzi, Francesca 2024 “Two sides of the same coin”, Chemistry World
• Goodwin, W. (2011). Structure, function, and protein taxonomy. Biology and Philosophy 26 (4), 533-545.
• Havstad, J. C. (2018). Messy chemical kinds. British Journal for the Philosophy of Science 69 (3), 719–743.
• Tahko, T. E. (2020). Where do you get your protein? or: biochemical realization. The British journal for the philosophy of science 71(3): 799-825.
• Tobin, E. (2010). Microstructuralism and macromolecules: the case of moonlighting proteins. Foundations of Chemistry 12, 41–54.
Francesca Bellazzi is a Postdoctoral researcher in the ERC Project Assembling Life (grant agreement n.101089326) at the University of Oslo. In her research, she investigates biochemical natural kinds and the relations between chemistry and biology.
Bình luận