Accurate structural modelling of protein-glycan recognition with GlycoWeave

Abstract

Protein-glycan recognition underlies diverse biological processes, yet accurate prediction of protein-glycan complex structures remains challenging owing to the chemical diversity, conformational flexibility and sparse experimental structural coverage of glycans. Here we present GlycoWeave, a glycan-specific diffusion framework that integrates chemically constrained conformational sampling, multiscale molecular representations and multi-source learning. By operating in internal-coordinate space, GlycoWeave preserves glycan connectivity and stereochemistry while efficiently exploring bound conformations. A heterogeneous equivariant network couples atom-level interaction geometry with monosaccharide-level structural context, whereas multi-source, multi-head training integrates experimental complexes with structures refined using classical and quantum mechanics-informed potentials. On a benchmark of 698 protein-glycan complexes, GlycoWeave achieves a 71.9% Top-25 high-quality success rate, compared with 19.2% for AlphaFold 3, while requiring only 0.34 s per sampled pose. GlycoWeave further preserves glycan structural validity, recovers native protein-glycan interactions and reproduces linkage-specific conformational preferences, maintaining high accuracy across diverse glycan architectures and protein environments. These results establish GlycoWeave as an accurate, efficient and chemically faithful framework for modelling protein-glycan recognition. GlycoWeave is freely available at https://cadd.zju.edu.cn/glycoweave.