  So far, more than 82,000 protein structures have been reported in the Protein
Data Bank, but the driving force and structures that allow for protein
functions have not been elucidated at the atomic level for even one protein. We
have been able to clarify that the inter-subunit hydrophobic interaction
driving the electrostatic opening of the pore in aquaporin 0 (AQP0). Aquaporins
are membrane channels for water and small non-ionic solutes found in animals,
plants, and microbes. The structures of aquaporins have high homology and
consist of homotetramers, each monomer of which has one pore for a water
channel. Each pore has two narrow portions: one is the narrowest constriction
region consisting of aromatic residues and an arginine (ar/R), and another is
two asparagine-proline-alanine (NPA) homolog portions. Here we show that an
inter-subunit hydrophobic interaction in AQP0 drives a stick portion consisting
of four amino acids toward the pore and the tip of the stick portion,
consisting of a nitrogen atom, opens the pore: that movement is the swing
mechanism (this http URL). The energetics and conformational change of amino
acids participating in the swing mechanism confirm this view. The swing
mechanism in which inter-subunit hydrophobic interactions in the tetramer drive
the on-off switching of the pore explains why aquaporins consist of tetramers.
Here, we report that experimental and molecular dynamics findings using various
mutants support this view of the swing mechanism. The finding that mutants of
amino acids in AQP2 corresponding to the stick of the swing mechanism cause
severe recessive nephrogenic diabetes insipidus (NDI) demonstrates the critical
role of the swing mechanism for the aquaporin function. We report first that
the inter-subunit hydrophobic interaction in aquaporin 0 drives the
electrostatic opening of the aquaporin pore at the atomic level.
