Developing and Benchmarking Sulfate and Sulfamate Force Field Parameters for Glycosaminoglycans via Ab Initio Molecular Dynamics Simulations
Glycosaminoglycans (GAGs) are negatively charged polysaccharides found on cell surfaces, where they regulate transport pathways of foreign molecules toward the cell. The structural and functional diversity of GAGs is largely attributed to varied sulfa-tion patterns along the polymer chains, which makes understanding their molecular recognition mechanisms crucial. Molecular dynamics (MD) simulations, with their un-matched microscopic perspective, have the potential to be a reference tool for exploring the patterns responsible for biologically relevant interactions. However, the capability of molecular dynamics models (i.e., force fields) used in biosimulations to accurately capture sulfation-specific interactions is not well established. In this work, we evalu-ate the performance of molecular dynamics force fields for sulfated GAGs by studying ion pairing of Ca2+ to sulfated moieties -- N-methylsulfamate and methylsulfate -- that resemble N- and O-sulfation found in GAGs, respectively. We tested nonpolariz-able (CHARMM36 and GLYCAM06), explicitly polarizable (Drude and AMOEBA), and implicitly polarizable through charge scaling (prosECCo75 and GLYCAM-ECC75) force fields. The Ca-sulfamate/sulfate interaction free energy profiles obtained with the tested force fields were compared against reference ab initio molecular dynamics (AIMD) simulations. AIMD reveals that the preferential Ca2+ binding mode to sul-fated GAG groups is solvent-shared pairing, and only the charge-scaled models agree satisfactorily with the AIMD data. All other force fields exhibit poorer performance, sometimes even qualitatively. Surprisingly, even explicitly polarizable force fields dis-play a notable shortfall in their performance, attributed to difficulties in their optimiza-tion and possible inherent limitations in depicting high-charge-density ion interactions accurately. Finally, the underperforming force fields lead to unrealistic aggregation of sulfated saccharides, qualitatively distorting our understanding of the soft glycocalyx environment. Our results highlight the importance of accurately treating electronic polarization in MD simulations of sulfated GAGs and caution against over-reliance on currently available models without thorough validation and optimization.