Abstract Accurate prediction of structure of protein–carbohydrate complexes remains a significant challenge in structural glycobiology, largely due to the flexibility of glycans and the shallow, hydrophilic nature of their binding sites. To address this issue, we developed a guided docking protocol that leverages Crystallographic Water Sites (CWS) to enhance glycan pose prediction using AutoDock Vina (ADV). By defining Waters Ideal Interactions (WII)—interaction hotspots derived from water molecules in apo structures—the protocol systematically rewards chemically meaningful receptor-ligand contacts during docking simulations. The WII Guided Approach (WIIGA) was benchmarked against a curated dataset of 30 high-quality protein–oligosaccharide complexes, which included ligands ranging from tetra- to nonasaccharides. Performance evaluation demonstrated that the guided protocol consistently outperformed conventional methods (ADV, Vina Carb (VC), Vina Carb with CH–π (VC CH–π) and GlycoTorch Vina (GTV)), delivering improved pose prediction accuracy. Our method proved robust even in the absence of holo structures and was effective in cross-docking drug-like glycomimetics. The protocol is easy to implement and broadly applicable to a wide range of glycan-binding proteins. These findings underscore the value of solvent-derived information for improving docking accuracy and support the use of guided approaches as a versatile tool for glyco-ligand modeling and structure-based design.
Lannot et al. (Wed,) studied this question.