  Protein-protein binding enables orderly and lawful biological
self-organization, and is therefore considered a miracle of nature.
Protein-protein binding is steered by electrostatic forces, hydrogen bonding,
van der Waals force, and hydrophobic interactions. Among these physical forces,
only the hydrophobic interactions can be considered as long-range
intermolecular attractions between proteins in intracellular and extracellular
fluid. Low-entropy regions of hydration shells around proteins drive
hydrophobic attraction among them that essentially coordinate protein-protein
docking in rotational-conformational space of mutual orientations at the
guidance stage of the binding. Here, an innovative method was developed for
identifying the low-entropy regions of hydration shells of given proteins, and
we discovered that the largest low-entropy regions of hydration shells on
proteins typically cover the binding sites. According to an analysis of
determined protein complex structures, shape matching between the largest
low-entropy hydration shell region of a protein and that of its partner at the
binding sites is revealed as a regular pattern. 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. A simple algorithm is developed to
precisely predict protein binding sites.
