Side-chain dynamics are critical for water permeation through aquaporin-1

¹ University of Washington

^* To whom correspondence should be addressed. E-mail: daggett{at}u.washington.edu.

Submitted on November 3, 2007
Revised on December 4, 2007
Accepted on 31 March 2008

	Abstract

Molecular dynamics simulations of aquaporin-1 embedded in a solvated lipid bilayer were performed to investigate the mechanism of water permeation. The 2.2 Å resolution crystal structure of the bovine protein was used for five independent trajectories, lasting between 4 and 10 ns. During the equilibration and preparatory steps in which the protein was held fixed, water molecules inside the water channel adopted the same positions as observed in the crystal structure but they did not pass through the channel, suggesting that the dynamic motion of the protein is critical for water permeation. When the protein atoms were allowed to move, the side chains of the two asparagines in the two conserved NPA (Asn-Pro-Ala) motifs near the center of the channel formed hydrogen bonds with water and helped water molecules move through the channel by actively aligning them for transport. The main-chain oxygen atoms, which were exposed to the pore surface in the crystal structure, also contributed to water transfer. Besides the constriction region observed in the crystal structure (Arg 197, Phe 58, His 182 and Cys 191), we found that His 76 and Val 155 act as a valve by dynamically blocking water permeation and helping control flow.

Key Words: aquaporin, membrane protein, molecular dynamics, protein dynamics, simulation, water channel