Structome-TM: Complementing dataset assembly for structural phylogenetics by addressing size-based biases

Abstract Harnessing the explosion of protein structure data to uncover deep evolutionary relationships requires effective comparison methods. While widely used global alignment techniques are powerful, they can fail to identify homologous structures that differ significantly in size or domain architecture. To address this limitation, we introduce Structome-TM, a web resource for assembling datasets for distance-based phylogenetic reconstruction. Making use of the Template Modeling score to prioritise local structural similarity, Structome-TM excels at identifying these otherwise obscured relationships, allowing users to build a comprehensive structural neighbourhood of proteins suitable for comparison. To facilitate this dataset assembly, the resource accepts Protein Data Bank identifiers, user-uploaded structure files, and protein sequences as inputs. When querying using a protein sequence, protein structures are predicted in real-time and their respective neighbourhoods determined, enabling analysis where experimentally determined structures may not be available. Through its user-friendly interface, Structome-TM provides a powerful and necessary approach for a more comprehensive exploration of protein evolution. This resource is freely available at: https://biosig.lab.uq.edu.au/structome_tm/.