Computational Prediction of Molecular Hydration Entropy with Hybrid Scaled Particle Theory and Free-Energy Perturbation Method

Abstract

Despite the importance of the knowledge of molecular hydration entropy (Δ<i>S</i>_hyd) in chemical and biological processes, the exact calculation of Δ<i><i>S</i></i>_hyd is very difficult, because of the complexity in solute–water interactions. Although free-energy perturbation (FEP) methods have been employed quite widely in the literature, the poor convergent behavior of the van der Waals interaction term in the potential function limited the accuracy and robustness. In this study, we propose a new method for estimating Δ<i><i>S</i></i>_hyd by means of combining the FEP approach and the scaled particle theory (or information theory) to separately calculate the electrostatic solute–water interaction term (Δ<i><i>S</i></i>_elec) and the hydrophobic contribution approximated by the cavity formation entropy (Δ<i><i>S</i></i>_cav), respectively. Decomposition of Δ<i><i>S</i></i>_hyd into Δ<i><i>S</i></i>_cav and Δ<i><i>S</i></i>_elec terms is found to be very effective with a substantial accuracy enhancement in Δ<i><i>S</i></i>_hyd estimation, when compared to the conventional full FEP calculations. Δ<i><i>S</i></i>_cav appears to dominate over Δ<i><i>S</i></i>_elec in magnitude, even in the case of polar solutes, implying that the major contribution to the entropic cost for hydration comes from the formation of a solvent-excluded volume. Our hybrid scaled particle theory and FEP method is thus found to enhance the accuracy of Δ<i><i>S</i></i>_hyd prediction by effectively complementing the conventional full FEP method