Alladi Ramakrishnan Hall

Nobel Prize in Chemistry 2024: Down the Rabbit Hole of Protein Structures - In pursuit of Design and Prediction

S Krishnaswamy

IMSc Chennai

Over the past several decades, Xray crystal structure determination has made significant
progress since the first protein structures of myoglobin and hemoglobin were determined which
led to Kendrew and Perutz getting the Nobel Prize in Chemistry in 1962. However, due to the
difficulties in experimental structure determination, despite the newer methods of High
Resolution Nuclear Magnetic Resonance and Cryo-Electron Microscopy, the publicly accessible
Protein Data Bank has mostly globular proteins. Consequently the progress of protein design
and prediction efforts have been necessarily constrained by the data available. However,
Baker's team from Harvard University after using their software Rosetta for design and Google
DeepMind’s predictive AlphaFold2 made considerable progress which resulted in the 2024
Nobel Prize in Chemistry for Baker, Hassabis and Jumper. The structural determination, design
and prediction of membrane proteins, fibrous proteins, intrinsically disordered proteins,
complexes of proteins and other macromolecules are still to be sufficiently explored. The
subsequent developments of RFDiffusion from Baker’s group and AlphaFold3 from DeepMind
are steps in the direction of design and prediction of oligomers and complexes. Like the Red
Queen tells Alice in Through the Looking Glass ''Now, here, you see, it takes all the running you
can do, to keep in the same place. If you want to get somewhere else, you must run at least
twice as fast as that!''. This can happen only when experimental structure determinations
covering the unexplored protein space are increased for which perhaps newer techniques or
approaches may be needed.