Computational structural analysis of Schistosoma integrins supports Smα1/Smβ1 as an RGD-compatible receptor candidate

Integrins are α/β heterodimeric adhesion receptors that mediate extracellular matrix recognition and intracellular signalling across metazoans. Although integrin homologues have been identified in parasitic helminths, their structural organization and ligand-binding properties remain poorly characterized. Here, we performed an integrative computational analysis to investigate the structural architecture and ligand compatibility of integrins in the human parasite Schistosoma mansoni . Comparative sequence analysis across medically important Schistosoma species identified a highly conserved β-integrin orthologue, Smβ1, together with four divergent α-integrin subunits. Structural prediction using AlphaFold3, RoseTTAFold and trRosetta indicated that the βI-containing region of Smβ1 retains the characteristic integrin fold and conserved MIDAS, ADMIDAS and SyMBS metal-coordination features. Candidate Smα/Smβ assemblies were evaluated using an integrated structural benchmarking framework incorporating fold conservation, stereochemical and backbone quality, VoroMQA/Voronoi packing, α/β-interface architecture, buried surface area and independent interface-context analyses. This framework prioritized Smα1/Smβ1 as the leading heterodimer candidate while retaining Smα3/Smβ1 as a structurally plausible alternative. Ligand-challenge modelling showed that Smα1/Smβ1 more readily reproduced the coupled RGD Arg-anchor and MIDAS-centred acidic-residue coordination observed in the human α5β1 benchmark than Smα3/Smβ1. Across expanded ligand ensembles, canonical and cyclic RGD-containing peptides were preferentially associated with RGD-like interaction geometries, whereas the RGE mutant and non-RGD controls showed reduced or absent canonical interaction features. In 100- and 200-ns molecular-dynamics trajectories, canonical RGD remained within a comparatively restricted receptor-associated conformational regime, whereas RGE underwent greater ligand displacement and contact-site structural mobility. MM/GBSA analysis over the 200 ns trajectory frames also supported more favourable energetic compatibility of RGD than RGE. An exploratory STRING analysis placed Smβ1 within a predicted adhesome-like network containing ILK-PINCH-Parvin and kinase-associated components. The combined analyses support Smα1/Smβ1 as a structurally plausible S. mansoni integrin candidate that is compatible with RGD-containing peptide engagement under the modelled conditions. These results provide experimentally testable hypotheses regarding α/β pairing, metal-dependent ligand recognition and integrin-associated signalling in schistosomes.