The interaction between amino acids (AAs) and hydration water is fundamental to protein folding and protein-protein interactions. Here, we proposed a hydrophobicity scale for AAs based on their computed free energetic cost of dewetting. This metric captures both entropic and enthalpic contributions of AA-water interactions and allows a systematic and intuitive classification of AAs. Using indirect umbrella sampling (INDUS), we rank individual AAs based on the relative magnitude of their dewetting free energies, from lowest (most hydrophobic) to highest (most hydrophilic). This new hydrophobicity scale is a starting point to evaluate different elements of water hydration behavior, and we focus here on the water structure and translational diffusivity of the hydration waters. While the latter is commonly used as a proxy for hydrophobicity, we show that its behavior is in fact nonmonotonic: hydrophobic residues show slow water diffusion due to highly structured hydration water networks, while highly hydrophilic residues have slow water diffusion due to strong hydrogen bonds with water despite less structured hydration networks. We extend our analysis of hydration properties to intrinsically disordered peptides with varied sequence patterning (sequences of proline/leucine and arginine/glutamic acid residues). We find that the hydration behavior of these peptides is highly context-dependent, with hydrophobic (hydrophilic) patches cooperatively enhancing hydrophobicity (hydrophilicity). These molecular insights of sequence-dependent hydration behaviors may be particularly impactful for the study of intrinsically disordered proteins implicated in liquid-liquid phase separation and aggregation, processes where AAs' hydration environments are complex and changing.
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