Interactions of nerve G-agents (sarin and soman) and their simulants DMMP (dimethyl methylphosphonate) and DIFP (diisopropyl fluorophosphate) with water and components of polyelectrolyte membranes are studied using ab initio calculations in conjunction with thermodynamic modeling using the conductor-like screening model for real solvents (COSMO-RS). To test reliability of COSMO-RS calculations, we measured the vapor-liquid equilibrium in DMMP-water mixtures and found quantitative agreement between computed and experimental results. Using COSMO-RS, we studied the interactions of phosphororganic agents with the characteristic fragments of perfluorinated and sulfonated polystyrene (sPS) polyelectrolytes, which are explored for protective clothing membranes. We found that both simulants, DIFP and DMMP, mimic the thermodynamic properties of G-agents reasonably well; however, there are certain specific differences that are discussed. We also suggested that sPS-based polyelectrolytes have less affinity for phosphorganic agents compared to prefluorinated polyelectrolytes similar to Nafion.