Effect of AQP4 and its palmitoylation on the permeability of exogenous reactive oxygen species: Insights from computational study

Aquaporin 4 (AQP4) facilitates the transport of reactive oxygen species (ROS). Both cancer cells and the ionizing radiation microenvironment can induce posttranslational modifications (PTMs) in AQP4, which may affect its permeability to ROS. Because this ROS diffusion process is rapid, microscopic, and instantaneous within and outside cells, conventional experimental methods are inadequate for elucidating the molecular mechanisms involved. In this study, computational methods were employed to investigate the permeability of exogenous ROS mediated by radiation in AQP4 at a molecular scale. We constructed a simulation system incorporating AQP4 and AQP4-Cysp13 in a complex lipid environment with ROS. Long-timescale molecular dynamics simulations were conducted to assess the structural stability of both AQP4 and AQP4-Cysp13. Free energy calculations were utilized to determine the ROS transport capability of the two AQP4 proteins. Computational electrophysiology and channel structural analysis quantitatively evaluated changes in ROS transport capacity under various radiation-induced transmembrane voltage microenvironments. Our findings demonstrate the distinct transport capabilities of AQP4 channels for water molecules and various types of ROS and reveal a decrease in transport efficiency when AQP4 undergoes palmitoylation modification. In addition, we have simulated the radiation-induced alteration of cell membrane voltage, which significantly affected the ROS transport capacity. We propose that this research will enhance the understanding of the molecular mechanisms governing the transport of exogenous ROS by AQP4 and elucidate the influence of palmitoylation on ROS transport. This study will also help clarify how different structural features of AQP4 affect the transport of exogenous ROS mediated by radiotherapy, thereby providing a theoretical molecular basis for the development of new treatment strategies that combine with radiotherapy.