Design and computational characterization of arginine-functionalized ZIF-8 as a pH-responsive oral insulin carrier.

This study presents a computational framework to evaluate arginine-modified ZIF-8 (ZIF-8@Arg) as a potential oral insulin delivery system. In contrast to unmodified metal-organic frameworks, the inclusion of arginine residues introduces guanidinium groups that enhance insulin interaction through electrostatic and hydrogen bonding effects. A combination of multiscale modeling techniques, including density functional theory (DFT), time-dependent DFT, molecular dynamics simulations, and topological analyses Atoms in Molecules (AIM) and Non-Covalent Interaction (NCI), was employed to characterize the molecular interface and environmental responsiveness. The results indicate improved binding stability at the ZIF-8@Arg-insulin interface, as well as pH-dependent structural adaptability, with swelling was observed under basic conditions. The activation energy for insulin release was calculated to be 15.39 kcal/mol. Solvation energy and partition coefficient (logP) analyses suggest favorable permeability characteristics. In silico Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling indicates low predicted toxicity and compatibility with oral administration. Overall, the findings support further investigation of ZIF-8@Arg as a functional MOF-based carrier with tunable release behavior and acceptable pharmacokinetic properties for oral peptide delivery.