Exploring the stability and pH-responsive behavior of the diphenylporphyrin@ExBOX⁴⁺ complex for controlled drug...

In this work, we explore the pH-responsive stability of the supramolecular host-guest complex formed by the tetracationic cyclophane ExBox⁴⁺ and diphenylporphyrin. This study builds upon the supramolecular concept originally introduced for ExBox⁴⁺-porphyrin systems by Stoddart and co-workers [1], providing a theoretical perspective on their pH-dependent behavior. We study how porphyrin protonation modulates geometry, binding interactions, and supramolecular behavior using a methodology that integrates density functional theory (DFT), energy decomposition analysis (EDA), non-covalent interaction (NCI) analysis, and molecular dynamics (MD) simulations. Our findings reveal that π-π stacking and electrostatic forces stabilize the neutral complex, whereas protonation breaks host-guest complementarity, weakening the assembly and allowing partial guest release. This set of methodologies provides a predictive tool for recognizing supramolecular assemblies, highlighting the potential of ExBox⁴⁺ as a pH-sensitive sequestering agent and showing how a combined DFT, EDA, NCI, and MD framework can serve as a practical approach to investigate controlled release processes in supramolecular systems.