Protein solvation: Site-specific hydrophilicity, hydrophobicity, counter ions, and interaction entropy.

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Solvation free energy is a driving force that plays an important role in the stability of biomolecular conformations. Currently, the implicit solvent model is widely used to calculate solvation energies of biomolecules such as proteins. However, for proteins, the implicit solvent calculation does not provide much detailed information since a protein is highly inhomogeneous on its surface. In this study, we develop an explicit solvent approach to protein solvation, which allows us to investigate detailed site-specific hydrophilicity and hydrophobicity, including the role of counter ions and intra-protein interactions. This approach facilitates the analysis of specific residue interactions with solvent molecules, extending the understanding of protein solubility to the energetic impacts of site-specific residue-solvent interactions. Our study showed that specific residue-solvent interactions are strongly influenced by the electrostatic environment created by its nearby residues, especially charged residues. In particular, charged residues on the protein surface are mainly responsible for the heterogeneity of the electrostatic environment of the protein surface, and they significantly affect the local distribution of water. In addition, counter ions change the local electrostatic environment and alter specific residue-water interactions. Neutral residues also interact with water, with polar residues being more prominent than nonpolar ones but contributing less to solvation energy than charged residues. This study illustrates an explicit solvent approach to protein solvation, which gives residue-specific contributions to protein solvation and provides detailed information on site-specific hydrophilicity and hydrophobicity.