Bias in, bias out - AlphaFold-Multimer and the structural complexity of protein interfaces

A structural understanding of protein-protein interactions is a key component of many facets of applied molecular biology research. AlphaFold-Multimer (AF-MM) provided a breakthrough in the ability to predict protein-protein interface structure. However, the available training data for this model and the resulting benchmarking and validation efforts show a bias toward interactions between more ordered regions of proteins. Here we highlight some of the successes and limitations of AF-MM and discuss available methods and future directions to enable balanced prediction of all interface types.