# Coarse-Grained Martini 3 Model of Chondroitin Sulfate A

## TL;DR

This paper introduces a new model for simulating chondroitin sulfate A using the Martini 3 force field, enabling efficient and accurate simulations of large biological systems.

## Contribution

A novel coarse-grained model of CSA compatible with Martini 3 is developed, enabling efficient simulations of large CSA systems.

## Key findings

- The model accurately reproduces atomistic properties of CSA disaccharide units and polymer chains.
- Three strategies are proposed to reduce overaggregation caused by electrostatics in CSA simulations.
- The model is compatible with the Martini Go̅ protein model and can simulate CSA–malaria adhesin interactions.

## Abstract

Chondroitin sulfate A (CSA) is a negatively charged linear
glycosaminoglycan
that 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, bonded interactions, and structural
polymer properties of CSA chains of different lengths. In particular,
for biologically relevant long chains and despite 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 Go̅ protein model was tested by
retrieving the force–response relationship 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 overaggregation. We provide at least three different
strategies to alleviate this issue, making use of a bigger bead for
sodium cations, reflecting their 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 enables predictive modeling
of CSA and potentially other chondroitin sulfates with the Martini
3 force field. In addition, this model provides insights for the further
development of coarse-grained models of highly charged systems.