Sulfation and Calcium Favor Compact Conformations of Chondroitin in Aqueous Solutions

[Image: see text] The effects of sulfation and calcium cations (Ca(2+)) on the atomic-resolution conformational properties of chondroitin carbohydrate polymers in aqueous solutions are not well studied owing to experimental challenges. Here, we compare all-atom explicit-solvent molecular dynamics simulations results for pairs of O-type (nonsulfated) and A-type (GlcNAc 4-O-sulfated) chondroitin 20-mers in 140 mM NaCl with and without Ca(2+) and find that both sulfation and Ca(2+) favor more compact polymer conformations. We also show that subtle differences in force-field parametrization can have dramatic effects on Ca(2+) binding to chondroitin carboxylate and sulfate functional groups and thereby determine Ca(2+)-mediated intra- and interstrand association. In addition to providing an atomic-resolution picture of the interaction of Ca(2+) with sulfated and nonsulfated chondroitin polymers, the molecular dynamics data emphasize the importance of careful force-field parametrization to balance ion–water and ion–chondroitin interactions and suggest additional parametrization efforts to tune interactions involving sulfate.