Driving Force for the Association of Hydrophobic Peptides: The Importance of Electrostatic Interactions in Coarse-Grained Water Models

The hydrophobic effect plays a central role in many biological processes, including protein folding and aggregation. The hydrophobic interaction between solutes, such as helical peptides, is believed to be of entropic origin and driven by the increase in the entropy of water due to association. In this work, we examine the association between peptides in water using several coarse-grained (CG) models, such as MARTINI (MAR), polarizable MARTINI (POL), and big multipole water (BMW) models, where four atomistic water molecules are grouped into a single CG unit. All models predict that a pair of helical peptides (Ala(20) and Leu(20)) has favorable association free energy. The BMW model is the only model, however, in which this association is entropy-driven, as has been previously established with atomistic simulations and experiments. The MAR and POL models, where the CG water particles do not have a quadrupole moment, predict an enthalpy-driven association, with a negligible entropy change upon association. Similarly, the association of two rigid cylinders in water is found to be enthalpy-driven when the water is described with the CG model of Shinoda et al. that includes a soft-core nonelectrostatic interaction, while BMW predicts an entropy-driven association. These results emphasize the importance of electrostatic interactions in water for the qualitative features of the thermodynamics of biophysical systems.