Coarse-Grained Model of Phytic Acid for Predicting the Supramolecular Architecture of Ionically Cross-Linked Chitosan Hydrogels.

Phytic acid is a polyphosphate whose ionized form is used as a cross-linking agent to formulate chitosan-based nanoparticles and hydrogels as carriers with remarkable adhesivity and biocompatibility. To predict the underlying cross-linking pattern responsible for the structural arrangement in the chitosan hydrogels, we put forth coarse-grained parametrization of the phytic acid compatible with the Martini 2.3P force field. The bonded parameters giving the distinctive representation of the phosphate substitutes to the myo-inositol ring of phytic acid are optimized by a structural comparison to the conformation sampled with the GROMOS 56ACARBO force field. The chitosan strand is coarse-grained following a similar approach, and the cross-interaction terms are optimized to reproduce the atomistic features of phytate-mediated cross-linking. The predicted binding motifs of the phytic acid-chitosan complexation enable us to rationalize the structural characteristics of the reticulated chitosan in a semi-dilute solution. The model describes a network topology affected by the phytic acid concentration and a nonmonotonous behavior of the mean pore size caused by a poor predilection for the parallel strand alignment near the charge neutralization of the phytic acid-chitosan complex.

Polymorphism of chitosan-based networks stabilized by phytate investigated by molecular dynamics simulations.

Chitosan can associate in the presence of polyphosphates into insoluble hydrogels capable of drug encapsulation and safe and efficient release. On the one hand, chitosan hydrogels were synthesized using the phytate anion as a crosslinking agent and were characterized by employing dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FTIR). On the other hand, an effective chitosan-phytate model with atomistic details was created to examine the underlying physical crosslinking pattern, and the structure and dynamics of the chitosan-phytate complex were systematically investigated by using molecular dynamics (MD) simulations. To harbor the crosslinker potential for obtaining chitosan-based hydrogels, the impact of the phytate concentration and the functional groups of the chitosan on the reticulation process was addressed. The phytate association was determined by the phosphates' capacity for H-bonding to the amine and hydroxyl groups belonging to two consecutive glucosidic units. The physical crosslinking pattern was determined by the number of chitosan chains bound by one phytate anion and the phytate orientation relative to the glucopyranose neighbors. Cross-linking of two up to six chitosan chains mediated by a phytate anion represented favorable states, and the number distribution of cross-linked chains depended on the phytate concentration. The circular distribution of the cross-linkable phosphates regulated the nearly isotropic orientation of the chitosan chains and phytate at the junction, and the variety of topological crosslinking demonstrated the phytate ion's potential for developing chitosan-based hydrogels with improved structural attributes.