(Un)folding host–microbe interactions. Can structural predictions reveal what lies beneath?

AlphaFold has transformed structural biology, providing unprecedented insights into protein folding, dynamics, and function. Extensions such as AlphaFold-Multimer now allow the prediction of protein-protein interactions, offering a powerful lens to explore complex molecular networks. While these approaches have inherent limitations and present unique challenges, they represent a promising addition to the toolkit for studying host-microbe interactions. In host-microbe systems, structural predictions could aid in dissecting molecular interfaces, uncovering symbiotic or pathogenic mechanisms, and generating hypotheses to guide experimental validation.We applied structural prediction tools to investigate two distinct host-microbe systems:- Midichloria mitochondrii and Ixodes ricinus. Midichloria are intracellular symbionts that colonize the tick mitochondria, with previous studies indicating a potential influence on the mitochondrial network. AlphaFold-Multimer helped to identify a potential molecular interaction that may explain this effect.- Borrelia burgdorferi and humans. Borrelia is a tick-borne pathogen responsible for Lyme disease. Although a few key interactions underlying infection and pathogenesis are already characterized, the full host-pathogen interactome remains unexplored. Constructing a comprehensive Borrelia-human protein-protein interactome could uncover novel mechanisms of pathogenesis and immune evasion.