Coordination-driven structural modulation of ligand confinement and biological response in calcium-alginate networks: A multiscale computational-experimental study

Abstract

Calcium-mediated coordination plays a central role in determining the structural and functional properties of alginate-based polymer networks. Here, we investigate how calcium stoichiometry modulates ligand confinement and emergent biological response in calcium-alginate systems using methyl jasmonate (MeJA) as a model bioactive compound. An integrated multiscale approach combining molecular dynamics simulations with physicochemical and cellular analyses was employed. Atomistic simulations revealed that increasing Ca²⁺ coordination density (Alg:Ca²⁺ 1:2) produces a more compact and energetically stabilized polymer network, characterized by reduced solvent-accessible surface area, lower radius of gyration, enhanced ion-mediated contacts, and decreased MeJA diffusion. These descriptors indicate tighter ligand confinement within a coordination-driven matrix. Experimental validation through ATR-FTIR, thermogravimetric, and calorimetric analyses confirmed enhanced structural cohesion and thermal stability in highly crosslinked formulations, supporting competitive coordination between MeJA carbonyl groups and Ca²⁺ ions. Importantly, these structural differences translated into distinct biological outcomes. Only formulations exhibiting higher coordination density induced significant cytotoxicity in AGS gastric cancer cells, demonstrating that modulation of matrix organization directly influences functional response. Collectively, this study establishes calcium coordination density as a tunable structural parameter controlling ligand dynamics and biological performance, highlighting the predictive value of molecular modeling for rational design of coordination-engineered biopolymer systems.

Keywords: Controlled molecular release; Multiscale molecular simulations; Nanocarrier engineering; Phytohormone bioactivity; Polymer–ion network dynamics.