LAUSR

We developed an approach to improve the lectin-binding affinity of an oligosaccharide by remodeling its conformational space in the precomplexed state. Using experimentally validated molecular dynamics simulation, we designed a Lewis X analog with an increased population of conformational species that were originally very minor but exclusively accessible to the target lectin without steric hindrance by modifying the non-reducing terminal galactose, which does not directly contact the lectin in the complex. This Lewis X mimetic showed 17 times higher affinity for the lectin than the native counterpart. Our approach, complementing the lectin-bound-state optimizations, offers an alternative strategy to create high-affinity oligosaccharides by increasing populations of on-pathway metastable conformers.