Comparison of Protein-Glycosaminoglycan Interactions in ff14sb/GLYCAM06j-1 and CHARMM36m Force Fields.

Abstract

Glycosaminoglycans (GAGs) are long, anionic polysaccharides abundant in the extracellular matrix and lysosomes, where their electrostatic interactions with proteins are essential for biological function. Computational studies of GAG-containing systems remain challenging due to their significant charge density and conformational flexibility. Here we benchmark two widely used force-fields, ff14SB/GLYCAM06j-1 and CHARMM36m, for three experimentally characterized protein-GAG complexes. Both force fields reproduce the key structural features of protein-GAG interactions, while GAG dynamics depend on protein charge, with CHARMM36m favoring broader surface exploration for highly positively charged proteins and AMBER enhancing mobility for less charged systems. Although protein flexibility is similarly described, ff14SB/GLYCAM06j-1 samples a broader GAG conformational space, and dissociation free energy profiles diverge for highly anionic GAGs, but remain comparable for moderately sulfated systems. In addition, we performed molecular dynamics simulations for all systems using the ff14SB/GLYCAM06j-1, CHARMM36m, and ff19SB/GLYCAM06j-1 force fields in a 15 Å solvent box. Structural and energetic analyses revealed no significant impact of the solvent box size on the examined descriptors. These results establish practical benchmarks for accurate atomistic simulations of GAG-protein assemblies and will inform future developments in biomolecular force fields.