  Plasmodium falciparum aquaglyceroporin (PfAQP) is a multifunctional membrane
protein in the plasma membrane of P. falciparum, the parasite that causes the
most severe form of malaria. The current literature has established the science
of PfAQP's structure, functions, and hydrogen-bonding interactions but left
unanswered the following fundamental question: Does glycerol modulate water
permeation through aquaglyceroporin that conducts both glycerol and water? This
paper provides an affirmative answer to this question of essential importance
to the protein's functions. On the basis of the chemical-potential profile of
glycerol from the extracellular bulk region, throughout PfAQP's conducting
channel, to the cytoplasmic bulk region, this study shows the existence of a
bound state of glycerol inside aquaglyceroporin's permeation pore, from which
the dissociation constant is approximately 14 microM. A glycerol molecule
occupying the bound state occludes the conducting pore through which permeating
molecules line up in single file by hydrogen-bonding with one another and with
the luminal residues of aquaglyceroporin. In this way, glycerol inhibits
permeation of water and other permeants through aquaglyceroporin. The
biological implications of this theory are discussed and shown to agree with
the existent in vitro data. It turns out that the structure of aquaglyceroporin
is perfect for the van der Waals interactions between the protein and glycerol
to cause the existence of the bound state deep inside the conducting pore and,
thus, to play an unexpected but significant role in aquaglyceroporin's
functions.
