Coarse-Graining Waters: Unveiling The Effective Hydrophilicity/Hydrophobicity of Individual Protein Atoms and The Roles of Waters’ Hydrogens

There have been many coarse-graining methods developed that aim to reduce the sizes of simulated systems and their computational costs. In this work, we develop a new coarse-graining method, called coarse-graining-delta (or δ-CG in short), that reduces the degrees of freedom of the potential energy surface by coarse-graining relative locations of atoms from their unit centers. Our method extends and generalizes the methods used in the coarse-grained normal mode analysis and enables us to study the roles of the individual removed atoms in a system, which have been difficult to study in molecular dynamics simulations. By applying δ-CG to coarse-grain three-point water molecules into single-point solvent particles, we successfully identify the effective hydrophilicity and hydrophobicity of all the individual protein atom types, which collectively correlate well with the known hydrophilic, hydrophobic, and amphipathic characteristics of amino acids. Moreover, our investigation shows that water’s hydrogens have two roles in interacting with protein atoms. First, water molecules adjust their poses around different amino acids and their atoms, and the statistical preferences of the hydrogen poses near the atoms determine the effective hydrophilicity and hydrophobicity of the atoms, which have not been successfully addressed before. Second, the collective dynamics of the hydrogens assist the water molecules in escaping from the potential energy wells of the hydrophilic atoms. Our method also shows that coarse-graining a system mathematically leads to breaking antisymmetry of the nonbonded interactions; as a result, two interacting coarse-grained units exert different forces on each other. Our study indicates that the accuracy of coarse-grained force fields, such as the MARTINI force field and the UNRES force field, can be improved in two ways: (i) refining their potential energy functions and coefficients by analyzing the coarse-grained potential energy surface using δ-CG, and (ii) introducing non-antisymmetric interactions.