Benchmark of Available Explicit Solvent Models in CHARMM36m to Characterize Glycosaminoglycans

Heparin is a highly sulfated glycosaminoglycan (GAG) with essential roles in anticoagulation, angiogenesis, cell signaling, and host–pathogen interactions, mediated largely through electrostatic binding to diverse protein targets. While the TIP3P water model is commonly used in molecular simulations of GAGs, the influence of solvent representation on HP structure within the CHARMM36m force field remains poorly understood. Here, we report 5 μs molecular dynamics simulations of an HP dodecamer in five explicit solvent models: TIP3P, TIP4P, TIP5P, SPC/E, and OPC. TIP3P and SPC/E yield stable HP conformations, whereas TIP4P, TIP5P, and OPC introduce greater structural variability. Comparison with GLYCAM06 reveals that CHARMM36m preserves global HP architecture but differs in sampling specific glycosidic linkages. These findings highlight the critical impact of water model choice on GAG conformational dynamics and offer practical guidance for the accurate simulation of sulfated carbohydrates.