From Protein Structure to Function with Bioinformatics.pdf

9 Protein Dynamics: From Structure to Function 225efficiency of water permeation is accomplished by providing a hydrogen bond complementarityinside the channel comparable to bulk water, thereby establishing a lowpermeation barrier (de Groot and Grubmüller 2001; Tajkhorshid et al. 2002). Thesimulations furthermore identified that the selectivity in these channels is accomplishedby a two-stage filter. The first stage of the filter is located in the central partof the channel at the conserved asparagine/proline/alanine (NPA) region; the secondstage is located on the extracellular face of the channel in the aromatic/arginine (ar/R)constriction region (Fig. 9.5). As water permeation takes place on the nanosecondtimescale, permeation coefficients can be directly computed from the simulations,and compared to experiment. Quantitative agreement was found between permeationcoefficients from experiment and simulation, thereby validating the simulations.A long standing question in aquaporin research has been the mechanism bywhich protons are excluded from the aqueous pores. The MD simulations addressingwater permeation revealed a pronounced water dipole orientation patternacross the channel, with the NPA region as its symmetry centre (de Groot andFig. 9.5 (a) Water molecules are strongly aligned inside the aquaporin-1 channel, with theirdipoles pointing away from the central NPA region (de Groot and Grubmüller 2001). The waterdipoles (yellow arrows) rotate by approximately 180 degrees while permeating though the AQP1pore. The red and blue colours indicate local electrostatic potential, negative and positive, respectively.(b) Hydrogen bond energies per water molecule (solid black lines) in AQP1 (left) and GlpF(right). Protein-water hydrogen bonds (green) compensate for the loss of water-water hydrogenbonds (cyan). The main protein-water interaction sites are the ar/R region and the NPA site