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

Abstract

Recent advances in AI-based protein structure modeling have yielded remarkable progress in predicting protein structures. Since 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, but until now a reliable structure-based tree building method has been elusive. Here, we demonstrate that the use of structure-based phylogenies can outperform sequence-based ones not only for distantly related proteins but also, remarkably, for more closely related ones. This is achieved by inferring trees from protein structures using a local structural alphabet, an approach robust to conformational changes that confound traditional structural distance measures. As an illustration, we used structures to decipher the evolutionary diversification of a particularly challenging family: the fast-evolving RRNPPA quorum sensing receptors enabling gram-positive bacteria, plasmids and bacteriophages to communicate and coordinate key behaviors such as sporulation, virulence, antibiotic resistance, conjugation or phage lysis/lysogeny decision. The advent of high-accuracy structural phylogenetics enables myriad of applications across biology, such as uncovering deeper evolutionary relationships, elucidating unknown protein functions, or refining the design of bioengineered molecules.

Tertiary-interaction characters enable fast, model-based structural phylogenetics beyond the twilight zone

“…The deepest, hardest to resolve relationships – the relationships of the bacterial phyla, of archaea and eukaryotes, and of different classes of viruses, may all become more accessible. However, it may also be that structural characters will be useful even for improving the resolution of shallower relationships, as reported by Moi et al (2023). We think it likely that structural phylogenetics will soon move from revolutionary to routine.…”

“…The creators of Foldseek have already taken one step in this direction with FoldTree, which uses Foldseek’s 3Di alphabet to structurally align protein structures and AA sequences, and then calculate a “Fident” (fraction identical) distance between the AA sequences between pairs of structures (Moi et al 2023). Although they obtain good results with this approach (higher taxonomic congruence and more ultrametricity), trees are estimated from distance matrices using FastME (NJ followed by NNI/SPR optimization for the minimum evolution tree; Lefort et al 2015), and therefore subject to the limitations discussed above.…”

Viroid-like colonists of human microbiomes

“…Classical phylogenetic tools cannot account for evolutionary signals from non-position-independent RNA secondary structure constraints 38 , consistent with the complexities in estimating trees from such families 39 . Further, recent advances in protein tertiary structure prediction may now allow for protein structure based phylogenetic reconstruction that may be tolerant of greater sequence divergence 40,41 . As such, definitive phylogenetic work on Obelisks might benefit from future tools that incorporate both evolutionary signals from RNA secondary structure conservation, and from structural alignment of predicted Oblin-1 “globule” tertiary structures.…”

How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

“…Program 458004906, CRC237 369799452/A25) and an FEBS Excellence Award. Figures were prepared using UCSF CHIMERAX, and FOLDTREE [162,163]. Open Access funding enabled and organized by Projekt DEAL.…”