PhD defence: Understanding Macromolecules and their Interactions - Computational Methods and Experimental Insights

Proteins are the key building blocks of life, driving all processes in our bodies, both in health and disease. To perform their numerous functions, they interact with other molecules like DNA, RNA and ligands. Understanding these interactions at the atomic level is crucial for developing medicines.

This thesis focusses on the interactions that proteins make with other molecules.

When AlphaFold made millions of predicted protein structures available, we noticed that they were missing their ligands. We created AlphaFill to add these missing molecules and provide a more complete biological story. We also created X-FRAGtor which places mini-ligands in hundreds of experimental structures in one go to speed up drug discovery. Many drug candidates and other ligands contain halogen atoms like chlorine that can make special interactions with proteins: we analysed these interactions in our PDB-REDO databank to better appreciate their importance.

Furthermore, we studied interactions of proteins with DNA and RNA. First, we created new algorithms to better model DNA and RNA in experimental structures. We then zoomed in on a rare type of DNA, base-J, which is found in parasites that cause e.g. African sleeping disease. Combining experimental and computational techniques, we made atomic models of proteins binding base-J which revealed new structural insights for combatting these parasites.

Finally, we dove into the “CHAOS” of human proteins by performing a comprehensive analysis of the messy parts in them. We find that such messy parts predominantly occur at both ends and suggest that they might not be as messy as thought.

Together, the insights and innovations bring us closer to understanding life’s building blocks and help scientists design new treatments.