Water dynamics around T₀ vs R₄ of hemoglobin from local hydrophobicity analysis.

This article focuses on analyzing the local hydration and hydrophobicity around tetrameric hemoglobin (Hb) in its T₀ (ligand-free) and R₄ (fully ligand-bound) conformational substates using molecular dynamics simulations. It introduces local hydrophobicity (LH) as a measure that captures both the presence and orientation of water molecules at protein interfaces, distinguishing it from solvent accessible surface area (SASA), which quantifies available solvent space. The study finds that LH and SASA are only mildly correlated and that hydration patterns differ between the T₀ and R₄ states, with hydration playing an essential role in the allosteric T₀ → R₄ transition of Hb. The results highlight that protein flexibility influences LH values and that water molecules can penetrate even buried interfacial regions, underscoring the importance of explicit water dynamics in understanding protein function and allostery.