As an example, we can illustrate how the human 60S ribosomal protein L19 shows up in the context of the PDB (PDB ID: 4UG0). The ribosome is a large molecular machine that the cell uses to print proteins, reading our genetic code as a blueprint, and it is built as a complex from a diverse set of proteins bound to large ribosomal RNA molecules. The structure that L19 forms in the PDB is then specific to the complex, and we know that ribosomal protein L19 does not adopt that structure free in solution, it folds that way only during the construction of the ribosome.
When AlphaFold2 predicts the structure of L19 it provides a single chain, but it does not predict the fold that protein would take on its own, it predicts the structure that this protein is likely to have when found in the PDB. This prediction is very accurate, but as you can see it recalls the structure without providing the context.
The nature of these predictions are important for users to understand because context is required for understanding protein behavior, and while AlphaFold2 provides a powerful tool for obtaining structures it becomes up to the user to provide the context. Essentially, when using AlphaFold2, data pipelines need to be built that can bring the context back, and understanding how AlphaFold2 works is key to that process.
We believe that with the right amount of caution, the potential of AlphaFold2 to increase the accuracy of structure-based computational methods in medicine is enormous. We are particularly excited about using AlphaFold2 to access protein structure as easily as genetic sequence across the entire tree of life. We’ve already begun to use this to extend the reach of Cyclica’s Ligand Design into infectious disease, animal models, agriculture and other areas that benefit from working with non-human proteomes.
Fig 1: Molecular visualizations of Ribosomal Protein L19 as found in the solved structure of the Human 80S Ribosome on the left, and in the AlphaFold2 prediction set on the right.
Dr. Robert Vernon, Senior Computational Scientist
Dr. Andreas Windemuth, Chief Science Officer
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