Epistructural tension accounts for the free-energy cost of imperfect protein hydration, involving water molecules with a shortage of hydrogen-bonding partnerships when compared with the bulk solvent. The binding hot spots along protein-protein interfaces are identified with residues that contribute significantly to the epistructural tension of the free protein units. Upon association, such residues either displace or become deprived of low-coordination vicinal water molecules. Thus, epistructural tension becomes a primary molecular marker for protein associations and a blueprint for drug design.
The epistructural tension of a protein is primarily promoted by packing defects in the structure that enable the partial confinement of water molecules at the protein-water interface. Such defects are known as dehydrons and constitute solvent-exposed backbone hydrogen bonds. The water molecules surrounding dehydrons can be easily displaced or transferred to the bulk with minimal or negative reversible work, and thus dehydrons are sticky, promoting their own dehydration and enhancing the epistructural tension. It thus follows that the epistructural tension defines the physical underpinnings of protein interactions from a solvent-centric perspective.
- A. Fernández, Epistructural tension promotes protein associations. Physical Review Letters 108, 188102 (2012)
- A. Fernández, Transformative Concepts for Drug Design: Target Wrapping (Springer-Verlag, Heidelberg, Germany, 2010), pages 217-223.
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