Molecular dynamics and COSMO-RS model of menthol–fatty acid deep eutectic solvents: thermodynamic, structural, and dynamics insights

Deep eutectic solvents (DESs) have emerged as sustainable alternatives to conventional solvents; however, our molecular-scale understanding of their intrinsic properties remains limited. In this study, we investigate menthol-fatty acid (valeric acid, enanthic acid, and pelargonic acid) DESs through a synergistic framework that combines molecular dynamics (MD) simulations, the conductor-like screening model (COSMO-RS) predictions, and Kirkwood-Buff integral (KBI) analysis. Our MD simulations reveal how the concentration and length of fatty acid chains influence the microscopic structure and dynamics within mixtures. COSMO-RS calculations provide predictive insights into activity coefficients and solvation tendencies, aligning closely with our atomistic results. Additionally, KBI analyses quantify preferential interactions, and isothermal compressibility, establishing a strong thermodynamic connection between microscopic ordering and macroscopic properties. Our findings demonstrate that subtle variations in fatty acid chain length affect the stability, heterogeneity, and transport behavior of these mixtures. This provides a rational approach for tuning their properties. Beyond these systems, the combined use of MD, COSMO-RS, and KBI methods presents a transferable and predictive protocol for designing DESs with tailored functionalities. This research enhances our understanding of the organization and thermodynamics of DESs, while also providing essential design principles to promote their application in bioprocessing and separation technologies. DES systems were designed using VMD and PACKMOL to arrange HBDs and HBAs. After performing energy minimization and equilibration at a temperature of 298.15 K, these systems were simulated under NPT conditions for 50 nanoseconds to allow for structural relaxation. Thermodynamic and solvation properties were estimated using COSMO-RS model, while electronic structure calculations were conducted using TURBOMOLE at the triple zeta valence potential (TZVP) basis set. This multiscale approach integrates molecular dynamics, and continuum solvation modelling to thoroughly characterize the structural and thermodynamic properties of menthol-fatty acid DESs.