gapTrick - Structural characterisation of protein-protein interactions using AlphaFold with multimeric templates

The structural characterisation of protein-protein interactions is a key step in understanding the functions of living cells. Here I show that AlphaFold3 often fails to predict protein complexes that are either weak, or dependent on the presence of a cofactor that is not included in a prediction. To address this problem, I developed gapTrick, an AlphaFold2-based approach that uses multimeric templates to improve prediction reliability. I show that gapTrick improves predictions of weak and incomplete complexes based on low-accuracy templates, such as separate protein models rigid-body fitted into a cryo-EM reconstruction. I also show that it identifies with very high precision residue-residue interactions, which are critical for complex formation and a very strong indicator of model correctness. The approach can aid in the interpretation of challenging experimental structures and the computational identification of protein-protein interactions. Availability and implementationThe gapTrick source code is available at https://github.com/gchojnowski/gapTrick and requires only a standard AlphaFold2 installation to run. The repository also provides a Colab notebook that can be used to run gapTrick without installing it on the users computer.