The Lewis oligosaccharides have generally been viewed as somewhat rigid structures, adopting a compact closed conformation at equilibrium, where a stable stacking interaction is formed between the fucose and galactose rings (Figure ). Although the presence of more open non-stacked structures has previously been suggested by both NMR and computational studies, this could not be confirmed. Recently, however, unusual conformations adopted by Lewis antigens Le x and sLe x were reported by Topin and co-workers. In this case, crystal structures of Le x and sLe x bound to pathogenic Ralstonia solanacearum lectin (RSL) were found to adopt poses distinct from the closed shape. Subsequent long time scale MD simulation of Le x in explicit solvent by Topin et al. These Le x simulations highlight the need for long timescale trajectories to characterize as fully as possible the ensemble of glycan structures. However, despite recent advances in hardware development and utilization, exhaustively characterizing the multi-microsecond landscapes to identify rare conformational states, 1 remains a time consuming task. Recently, enhanced sampling MD techniques have been applied to the challenge of exploring carbohydrate conformation. Here, we map out the conformational landscape of Lewis oligosaccharides in aqueous solution, introducing and applying a computationally efficient variant of our earlier biased MD method. We term this variant multi-dimensional swarmenhanced sampling molecular dynamics (msesMD). We first assess the ability of msesMD to explore sLe a conformations in explicit aqueous solvent, comparing with multi-microsecond unbiased MD simulations, umbrella sampling and accelerated molecular dynamics (aMD). We then apply both msesMD and multi-microsecond unbiased MD simulations to investigate the ability of sLe x and the unmodified Lewis cores, Le a and Le x , to adopt non-closed conformations in aqueous solution.