Cracking the code of cellular protein–protein interactions: Alphafold and whole‐cell crosslinking to the rescue

Integration of experimental and computational methods is crucial to better understanding protein–protein interactions (PPIs), ideally in their cellular context. In their recent work, Rappsilber and colleagues (O'Reilly et al, 2023) identified bacterial PPIs using an array of approaches. They combined whole‐cell crosslinking, co‐fractionation mass spectrometry, and open‐source data mining with artificial intelligence (AI)‐based structure prediction of PPIs in the well‐studied organism Bacillus subtilis. This innovative approach reveals architectural knowledge for in‐cell PPIs that are often lost upon cell lysis, making it applicable to genetically intractable organisms such as pathogenic bacteria.