Accurate structure prediction of biomolecular interactions with AlphaFold 3

Accurate structure prediction of biomolecular interactions with AlphaFold 3

2024 | Josh Abramson, Jonas Adler, Jack Dunger, Richard Evans, Tim Green, Alexander Pritzel, Olaf Ronneberger, Lindsay Willmore, Andrew J. Ballard, Joshua Bambrick, Sebastian W. Bodenstein, David A. Evans, Chia-Chun Hung, Michael O'Neill, David Reiman, Kathryn Tunyasuvunakool, Zachary Wu, Akvilė Žemgulytė, Eirini Arvaniti, Charles Beattie, Ottavia Bertolli, Alex Bridgland, Alexey Cherepanov, Miles Congreve, Alexander I. Cowen-Rivers, Andrew Cowie, Michael Figurnov, Fabian B. Fuchs, Hannah Gladman, Rishub Jain, Yousuf A. Khan, Caroline M. R. Low, Kuba Perlin, Anna Potapenko, Pascal Savy, Sukhdeep Singh, Adrian Stecula, Ashok Thillaisundaram, Catherine Tong, Sergei Yakneen, Ellen D. Zhong, Michal Zielinski, Augustin Židek, Victor Bapst, Pushmeet Kohli, Max Jaderberg, Demis Hassabis & John M. Jumper
AlphaFold 3 is a deep learning model that significantly improves the accuracy of predicting the structures of biomolecular complexes, including proteins, nucleic acids, small molecules, ions, and modified residues. The model uses an updated diffusion-based architecture, which allows for more accurate predictions across a wide range of biomolecular interactions. Compared to previous specialized tools, AlphaFold 3 demonstrates higher accuracy in predicting protein-ligand interactions, protein-nucleic acid interactions, and antibody-antigen interactions. The model's architecture includes a Pairformer Module that replaces the Evoformer from AlphaFold 2, and a Diffusion Module that directly predicts raw atom coordinates. This approach allows the model to handle a wide variety of chemical structures without excessive special casing. The model also includes confidence measures that predict atom-level and pairwise errors in the final structures. These measures are based on the predicted structures and help in assessing the reliability of the predictions. AlphaFold 3 was evaluated on various benchmarks, including the PoseBusters benchmark set for protein-ligand interfaces, and it outperformed classical docking tools like Vina and RoseTTAFold All-Atom. The model also showed improved accuracy in predicting protein-nucleic acid complexes and RNA structures compared to other methods. Despite its improvements, AlphaFold 3 has some limitations, including issues with stereochemistry, hallucinations in disordered regions, and the inability to predict dynamic behavior of biomolecular systems. The model's performance is also affected by the number of training samples and the complexity of the interactions being predicted. However, the model's ability to handle a wide range of biomolecular interactions within a unified framework demonstrates the potential of deep learning in accurately predicting biomolecular structures. The development of AlphaFold 3 highlights the importance of deep learning in advancing the field of structural biology and has the potential to significantly reduce the amount of data required for accurate predictions.AlphaFold 3 is a deep learning model that significantly improves the accuracy of predicting the structures of biomolecular complexes, including proteins, nucleic acids, small molecules, ions, and modified residues. The model uses an updated diffusion-based architecture, which allows for more accurate predictions across a wide range of biomolecular interactions. Compared to previous specialized tools, AlphaFold 3 demonstrates higher accuracy in predicting protein-ligand interactions, protein-nucleic acid interactions, and antibody-antigen interactions. The model's architecture includes a Pairformer Module that replaces the Evoformer from AlphaFold 2, and a Diffusion Module that directly predicts raw atom coordinates. This approach allows the model to handle a wide variety of chemical structures without excessive special casing. The model also includes confidence measures that predict atom-level and pairwise errors in the final structures. These measures are based on the predicted structures and help in assessing the reliability of the predictions. AlphaFold 3 was evaluated on various benchmarks, including the PoseBusters benchmark set for protein-ligand interfaces, and it outperformed classical docking tools like Vina and RoseTTAFold All-Atom. The model also showed improved accuracy in predicting protein-nucleic acid complexes and RNA structures compared to other methods. Despite its improvements, AlphaFold 3 has some limitations, including issues with stereochemistry, hallucinations in disordered regions, and the inability to predict dynamic behavior of biomolecular systems. The model's performance is also affected by the number of training samples and the complexity of the interactions being predicted. However, the model's ability to handle a wide range of biomolecular interactions within a unified framework demonstrates the potential of deep learning in accurately predicting biomolecular structures. The development of AlphaFold 3 highlights the importance of deep learning in advancing the field of structural biology and has the potential to significantly reduce the amount of data required for accurate predictions.
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