We first note that free energy surface predicted for the Neu5Acα(2-3)Gal linkage via the triplicate 1 s and 10 s simulations are very similar (Figure ), suggesting good sampling on both timescales, due to a lack of intramolecular hindrance. We next consider the free energy surfaces of the Fucα(14)GlcNAc and Galβ(13)GlcNAc glycosidic linkages, labelling minima found on these surfaces as F and G regions respectively. Based on the first 1 s of the trajectories (referred to as the triplicate 1 s trajectories from this point), sLe a samples mainly around its initial closed conformational state, occupying the regions F 1 and G 1 (Figure ). This closed conformer is denoted from this point as the C state. Although no X-ray structure of sLe a could be found in the RCSB Protein Data Bank , we note that this C state appears to correspond to all observed Le a conformations in protein-bound crystal structures (Supporting Information, Table ). From the triplicate 1 s simulations, less frequently occupied conformations in nonclosed geometries are also predicted, denoted F 2-3 and G 2-3 respectively (Figure ). These open conformers tend to maintain partial interactions between the fucose and galactose rings; in certain cases these residues can orient themselves into a near perpendicular arrangement (Figure ), distinct from the parallel stacking of the closed state (Figure ). where no open conformers were detected. msesMD simulation. We compare these unbiased 1 s and 10 s MD simulations with a 245 ns msesMD simulation, using a swarm of eight coupled replicas of sLe a in explicit solvent, interacting via their proximity in the values of the six glycosidic torsion angles. Again we observe that the flexible Neu5Ac23)Gal linkage is readily sampled, with similar free energy landscapes to both the unbiased 1 s and 10 s simulations (Figure ). However, the msesMD free energy surfaces of the core Fucα(14)GlcNAc and Galβ(13)GlcNAc linkages of sLe a correspond considerably more closely to the full 10 s simulations than the first 1 s of MD, with broad sampling of the F 1-4 and G 1-4 low energy regions. The enhanced coverage of open forms by the swarm replicas is clearly shown by the sampling of ψ values for both glycosidic linkages (Figure ). Interestingly, on the Galβ(13)GlcNAc free energy surface obtained via msesMD, an additional low energy region is identified, which we denote G 5 (Figure ).