Spatial Layouts of Low-Entropy Hydration Shells Guide Protein Binding.

Protein-protein binding enables orderly biological self-organization and is therefore considered a miracle of nature. Protein‒protein binding is driven by electrostatic forces, hydrogen bonding, van der Waals force, and hydrophobic interactions. Among these physical forces, only hydrophobic interactions can be considered long-range intermolecular attractions between proteins due to the electrostatic shielding of surrounding water molecules. Low-entropy hydration shells around proteins drive hydrophobic attraction among them that essentially coordinate protein‒protein binding. Here, an innovative method is developed for identifying low-entropy regions of hydration shells of proteins by screening off pseudohydrophilic groups on protein surfaces and revealing that large low-entropy regions of the hydration shells typically cover the binding sites of individual proteins. According to an analysis of determined protein complex structures, shape matching between a large low-entropy hydration shell region of a protein and that of its partner at the binding sites is revealed as a universal law. Protein‒protein binding is thus found to be mainly guided by hydrophobic collapse between the shape-matched low-entropy hydration shells that is verified by bioinformatics analyses of hundreds of structures of protein complexes, which cover four test systems. A simple algorithm is proposed to accurately predict protein binding sites.