A single aquaporin protein lets one billion water molecules into a cell each second. It is one of the "fastest" channels in all of biology. Each water flows through in single file, while H+, sodium, potassium, and other ions are excluded. What explains this remarkable selectivity? Two clever protein filters. But first: Each aquaporin protein is made from six alpha-helices that run back and forth through the cell membrane. These helices form an hourglass shape so that the channel is cone-shaped at either end and extremely narrow in the middle. The two ends of the protein also mirror each other, with their point of symmetry occurring at the narrowest part of the channel. It's thought that modern aquaporins evolved through a gene duplication event. Now let's zoom in a bit and look at the two filters within aquaporin that account for its extreme selectivity. Water can flow either way through the channel, so we'll imagine that we're moving from OUTSIDE the cell to INSIDE the cell. The first filter we encounter is called the ar/R filter. This is a cluster of polar and charged amino acids that point inside the aquaporin channel. These four amino acids are *usually* arginine (+ charge), histidine (polar), and two bulky amino acids like phenylalanine and tryptophan. These four amino acids come together to restrict the middle of the pore, making it just wide enough for a single water molecule to pass. The positively charged arginine also helps "stabilize" water molecules while forcing away sodium ions or protons. The second filter encountered on our journey into the cell is called the NPA motif (short for asparagine–proline–alanine). There are two of them inside each aquaporin. These two protein motifs point at each other in the center of the aquaporin. As a water molecule passes the ar/R filter and moves deeper into the channel, it forms hydrogen bonds with the asparagine amino acid in the first NPA motif. But because the two motifs are oriented in opposite directions, the local electric field at the channel’s midpoint next forces each water molecule to rotate 180° and latch onto the asparagine in the second NPA motif. In other words, each water molecule gets flipped around inside the aquaporin channel. This "flipping" is important because it breaks the water molecules free from any hitch-hiking protons. It acts as the final filter.