Structural phylogenetics unravels the evolutionary diversification of communication systems in gram-positive bacteria and their viruses

Abstract Recent advances in artificial-intelligence-based protein structure modeling have yielded remarkable progress in predicting protein structures. Because structures are constrained by their biological function, their geometry tends to evolve more slowly than the underlying amino acids sequences. This feature of structures could in principle be used to reconstruct phylogenetic trees over longer evolutionary timescales than sequence-based approaches; however, until now, a reliable structure-based tree-building method has been elusive. Here, we introduce a rigorous framework for empirical tree accuracy evaluation and tested multiple approaches using sequence and structure information. The best results were obtained by inferring trees from sequences aligned using a local structural alphabet—an approach robust to conformational changes that confound traditional structural distance measures. We illustrate the power of structure-informed phylogenetics by deciphering the evolutionary diversification of a particularly challenging family: the fast-evolving RRNPPA quorum-sensing receptors. We were able to propose a more parsimonious evolutionary history for this critical protein family that enables gram-positive bacteria, plasmids and bacteriophages to communicate and coordinate key behaviors. The advent of high-accuracy structural phylogenetics enables a myriad of applications across biology, such as uncovering deeper evolutionary relationships, elucidating unknown protein functions or refining the design of bioengineered molecules.