Coarse-grained Martini 3 model of chondroitin sulfate A

Abstract

Chondroitin sulfate A (CSA) is a negatively charged linear glycosaminoglycan which plays a vital role in many biological processes. Research on CSA has been challenging due to its size, chemical heterogeneity, and multitude of binding partners. To address these issues, we developed a model of CSA for coarse-grained molecular dynamics simulations based on the Martini 3 force-field. We demonstrate that this model is capable of reproducing atomistic properties of the repeating CSA disaccharide unit, including its molecular volume and bonded interactions, and structural polymer properties of CSA chains of different lengths. In particular, for biologically-relevant long chains and despite of using an explicit solvent, the computational cost is significantly reduced, relative to the cost equivalent atomistic simulations would require. The compatibility of the model with the Martini G[o] protein model was tested by retrieving the forceresponse of the CSA-malaria adhesin VAR2CSA complex. Importantly, we explored the influence of electrostatics on CSA aggregation. We show that the default Martini 3 parameters lead to over-aggregation. We provide at least three different strategies to alleviate this issue, making use of a bigger bead for sodium cations, reflecting its hydration shell, partial ionic charges, as a mean-field resource to take into account electronic polarizability, and, optionally, particle-mesh Ewald summation as a more robust treatment of long-range electrostatics. Our model opens the door for predictive modeling of CSA and potentially other chondroitin sulfates. In addition, this model provides insights for the further development of coarse-grained models of highly-charged systems.