Can Electrostatic Solvation Entropy Predict Skin Irritation Potential from Surfactants?

Surfactants are essential in industrial and biological applications, but their interactions with biological systems, particularly skin, often lead to irritation. Understanding the molecular determinants of surfactant-induced skin irritation requires a detailed analysis of the solvation thermodynamics. In this study, we employ all-atom free energy perturbation molecular dynamics (FEP/MD) simulations to investigate the solvation free energy and entropy of sodium lauryl ether sulfate (SLES) surfactants with varying ethoxylate spacer lengths C₁₂H₂₅(OCH₂CH₂)_<i>x</i>OSO₃Na (where <i>x</i> = 1-3). The solvation free energy is partitioned into van der Waals (vdW) and electrostatic contributions, revealing that (1) vdW interactions become increasingly unfavorable with longer hydrophobic spacers due to entropic penalties for water ordering; (2) electrostatic contributions dominate solvation and grow more favorable with extended ethoxylation, driven by charge delocalization and reduced water structuring around headgroups. Temperature-dependent analyses show that electrostatic solvation entropy becomes less negative with longer spacers, indicating a chaotropic (water-structure-breaking) effect. This trend correlates with experimental observations of a reduced critical micelle concentration (CMC) and attenuated skin irritation, supporting the monomer penetration theory. Our results suggest that electrostatic entropy serves as a predictive descriptor for skin irritation potential, providing a molecular framework for designing milder surfactants. These insights bridge computational thermodynamics with practical applications in personal care and pharmaceutical formulations.