Aquaporins pp 57-76 | Cite as

Dynamics and Energetics of Permeation Through Aquaporins. What Do We Learn from Molecular Dynamics Simulations?

  • Jochen S. Hub
  • Helmut Grubmüller
  • Bert L. de GrootEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 190)

Aquaporins (AQPs) are a family of integral membrane proteins, which facilitate the rapid and yet highly selective flux of water and other small solutes across biological membranes. Molecular dynamics (MD) simulations contributed substantially to the understanding of the molecular mechanisms that underlie this remarkable efficiency and selectivity of aquaporin channels. This chapter reviews the current state of MD simulations of aquaporins and related aquaglyceroporins as well as the insights these simulations have provided. The mechanism of water permeation through AQPs and methods to determine channel permeabilities from simulations are described. Protons are strictly excluded from AQPs by a large electrostatic barrier and not by an interruption of the Grotthuss mechanism inside the pore. Both the protein's electric field and desolvation effects contribute to this barrier. Permeation of apolar gas molecules such as CO2 through AQPs is accompanied by a large energetic barrier and thus can only be expected in membranes with a low intrinsic gas permeability. Additionally, the insights from simulations into the mechanism of glycerol permeation through the glycerol facilitator GlpF from E. coli are summarized. Finally, MD simulations are discussed that revealed that the aro-matic/arginine constriction region is generally the filter for uncharged solutes, and that AQP selectivity is controlled by a hydrophobic effect and steric restraints.


Water Permeation Uncharged Solute Grotthuss Mechanism Desolvation Effect Hydrogen Bond Partner 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Beitz E, Wu B, Holm LM, Schultz JE, Zeuthen T (2006) Point mutations in the aromatic/arginine region in aquaporin 1 allow passage of urea, glycerol, ammonia, and protons. Proc Natl Acad Sci USA 103:269–274PubMedCrossRefGoogle Scholar
  2. Blank ME, Ehmke H (2003) Aquaporin-1 and HCO3(−)−Cl(−) transporter-mediated transport of CO2 across the human erythrocyte membrane. J Physiol 550:2:419–429PubMedCrossRefGoogle Scholar
  3. Borgnia MJ, Agre P (2001) Recontitution and functional comparison of purified GlpF and AqpZ, the glycerol and water channels from Eschericia coli. Proc Natl Acad Sci USA 98:2888–2893PubMedCrossRefGoogle Scholar
  4. Burykin A, Warshel A (2003) What really prevents proton transport through aquaporin? Charge self-energy versus proton wire proposals. Biophys1 J 85:3696–3706Google Scholar
  5. Burykin A, Warshel A (2004) On the origin of the electrostatic barrier for proton transport in aquaporin. FEBS Lett 570:41–46PubMedCrossRefGoogle Scholar
  6. Chakrabarti N, Roux B, Pomes R (2004a) Structural determinants of proton blockage in aquapor-ins. J Mol Biol 343:493–510CrossRefGoogle Scholar
  7. Chakrabarti N, Tajkhorshid E, Roux B, Pomes R (2004b) Molecular basis of proton blockage in aquaporins. Structure 12:65–74CrossRefGoogle Scholar
  8. Chen H, Wu Y, Voth GA (2006) Origins of proton transport behavior from selectivity domain mutations of the aquaporin-1 channel. Biophys J 90:L73–L75PubMedCrossRefGoogle Scholar
  9. Cooper GJ, Boron WF (1998) Effect of PCMBS on CO2 permeability of Xenopus oocytes expressing aquaporin 1 or its C189S mutant. Am J Physiol 275:C1481–C1486PubMedGoogle Scholar
  10. de Groot BL, Grubmüller H (2001) Water permeation across biological membranes:mechanism and dynamics of aquaporin-1 and GlpF. Science 294:2353–2357PubMedCrossRefGoogle Scholar
  11. de Groot BL, Grubmüller H (2005) The dynamics and energetics of water permeation and proton exclusion in aquaporins. Curr Opin Struct Biol 15:176–183PubMedCrossRefGoogle Scholar
  12. de Groot BL, Engel A, Grubmüller H (2001) A refined structure of human Aquaporin-1. FEBS Lett 504:206–211PubMedCrossRefGoogle Scholar
  13. de Groot BL, Tieleman DP, Pohl P, Grubmüller H (2002) Water permeation through gramicidin A:desformylation and the double helix; a molecular dynamics study. Biophys J. 82:2934–2942PubMedGoogle Scholar
  14. de Groot BL, Frigato T, Helms V, Grubmüller H (2003) The mechanism of proton exclusion in the aquaporin-1 water channel. J Mol Biol 333:279–293PubMedCrossRefGoogle Scholar
  15. de Grotthuss CJT (1806) Sur la décomposition de l'eau et des corps qu'elle tient en dissolution à l'aide de l'électricité galvanique. Ann Chim LVIII:54–74Google Scholar
  16. Endeward V, Musa-Aziz R, Cooper GJ, Chen L-M, Pelletier MF, Virkki LV, Supuran CT, King LS, Boron WF, Gros G (2006) Evidence that aquaporin 1 is a major pathway for CO2 transport across the human erythrocyte membrane. FASEB J 20:1974–1981PubMedCrossRefGoogle Scholar
  17. Engel A, Stahlberg H (2002) Aquaglyceroporins: channel proteins with a conserved core, multiple functions and variable surfaces. Int. Rev. Cytol.215:75–104PubMedCrossRefGoogle Scholar
  18. Fang X, Yang B, Matthay MA, Verkman AS (2002) Evidence against aquaporin-1-dependent CO2 permeability in lung and kidney. J Physiol 542:63–69PubMedCrossRefGoogle Scholar
  19. Finkelstein A (1987) Water movement through lipid bilayers, pores, and plasma membranes. Wiley, New YorkGoogle Scholar
  20. Fu D, Libson A, Miercke LJ, Weitzman C, Nollert P, Krucinski J, Stroud RM (2000) Structure of a glycerol-conducting channel and the basis for its selectivity. Science 290:481–486PubMedCrossRefGoogle Scholar
  21. Gonen T, Sliz P, Kistler J, Cheng Y, Walz T (2004) Aquaporin-0 membrane junctions reveal the structure of a closed water pore. Nature 429:193–197PubMedCrossRefGoogle Scholar
  22. Hashido M, Ikeguchi M, Kidera A (2005) Comparative simulations of aquaporin family: AQP1, AQPZ, AQP0 and GlpF. FEBS Lett 579:5549–5552PubMedCrossRefGoogle Scholar
  23. Hashido M, Kidera A, Ikeguchi M (2007) Water transport in aquaporins: osmotic permeability matrix analysis of molecular dynamics simulations. Biophys J 93:373–385PubMedCrossRefGoogle Scholar
  24. Heller KB, Lin EC, Wilson TH (1980) Substrate-specificity and transport-properties of the glycerol facilitator of Eschericia coli. J Bacteriol 144:274–278PubMedGoogle Scholar
  25. Hénin J, Tajkhorshid E, Schulten K, Chipot C (2008) Diffusion of glycerol through Escherichia coli aquaglyceroporin GlpF. Biophys J 94:832–839PubMedCrossRefGoogle Scholar
  26. Heymann JB, Engel A (2000) Structural clues in the sequences of the aquaporins. J Mol Biol 295:1039–1053PubMedCrossRefGoogle Scholar
  27. Hiroaki Y, Tani K, Kamegawa A, Gyobu N, Nishikawa K, Suzuki H, Walz T, Sasaki S, Mitsuoka K, Kimura K, Mizoguchi A, Fujiyoshi Y (2006) Implications of the aquaporin-4 structure on array formation and cell adhesion. J Mol Biol 355:625–639CrossRefGoogle Scholar
  28. Holm LM, Jahn TP, Møller ALB, Schjoerring JK, Ferri D, Klaerke DA, Zeuthen T (2005) NH3 and NH4 + permeability in aquaporin-expressing Xenopus oocytes. Pflugers Arch 450:415–428PubMedCrossRefGoogle Scholar
  29. Hub JS, de Groot BL (2006) Does CO2 permeate through Aquaporin-1? Biophys J 91:842–848PubMedCrossRefGoogle Scholar
  30. Hub JS, de Groot BL (2008) Mechanism of selectivity in aquaporins and aquaglyceroporins. Proc Natl Acad Sci USA 105:1198–1203PubMedCrossRefGoogle Scholar
  31. Ilan B, Tajkhorshid E, Schulten K, Voth GA (2004) The mechanism of proton exclusion in aqua-porin channels. Proteins 55:223–228PubMedCrossRefGoogle Scholar
  32. Jensen MØ, Mouritsen OG (2006) Single-channel water permeabilities of Escherichia coli aqua-porins AqpZ and GlpF. Biophys J 90:2270–2284PubMedCrossRefGoogle Scholar
  33. Jensen MØ, Tajkhorshid E, Schulten K (2001) The mechanism of glycerol conduction in aquaglyc-eroporins. Structure 9:1083–1093PubMedCrossRefGoogle Scholar
  34. Jensen MØ, Park S, Tajkhorshid E, Schulten K (2002) Energetics of glycerol conduction through aquaglyceroporin GlpF. Proc Natl Acad Sci USA 99:6731–6736PubMedCrossRefGoogle Scholar
  35. Jensen MØ, Tajkhorshid E, Schulten K (2003) Electrostatic tuning of permeation and selectivity in aquaporin water channels. Biophys J 85:2884–2899PubMedCrossRefGoogle Scholar
  36. Jung JS, Preston GM, Smith BL, Guggino WB, Agre P (1994) Molecular structure of the water channel through aquaporin CHIP — the hourglass model. J Biol Chem 269:14648–14654PubMedGoogle Scholar
  37. Kato M, Pisliakov AV, Warshel A (2006) The barrier for proton transport in aquaporins as a challenge for electrostatic models: the role of protein relaxation in mutational calculations. Proteins 64:829–844PubMedCrossRefGoogle Scholar
  38. Lee JK, Kozono D, Remis J, Kitagawa Y, Agre P, Stroud RM (2005) Structural basis for conductance by the archaeal aquaporin AqpM at 1.68 A. Proc Natl Acad Sci USA 102:18932–18937PubMedCrossRefGoogle Scholar
  39. Maurel C, Reizer J, Schroeder JI, Chrispeels MJ, Saier MH (1994) Functional characterization of the Eschericia coli glycerol facilitator, GlpF, in Xenopus oocytes. J Biol Chem 269: 11869–11872PubMedGoogle Scholar
  40. Murata K, Mitsuoka K, Walz T, Agre P, Heymann JB, Engel A, Fujiyoshi Y (2000) Structural determinants of water permeation through aquaporin-1. Nature 407:599–605PubMedCrossRefGoogle Scholar
  41. Nakhoul NL, Davis BA, Romero MF, Boron WF (1998) Effect of expressing the water channel aquaporin-1 on the CO2 permeability of Xenopus oocytes. Am J Physiol Cell Physiol 274:C543–C548Google Scholar
  42. Prasad GVR, Coury LA, Finn F, Zeidel ML (1998) Reconstituted aquaporin 1 water channels transport co2 across membranes. J Biol Chem 273:33123–33126PubMedCrossRefGoogle Scholar
  43. Preston GM, Carroll TP, Guggino WB, Agre P (1992) Appearance of water channels in Xenopus oocytes expressing red-cell CHIP28 protein. Science 256:385–387PubMedCrossRefGoogle Scholar
  44. Savage DF, Egea PF, Robles-Colmenares Y, O'Connell JDI, Stroud RM (2003) Architecture and selectivity in aquaporins:2.5Å X-ray structure of aquaporin Z. PLoS Biol. 1:e72PubMedCrossRefGoogle Scholar
  45. Sui H, Han B-G, Lee JK, Walian P, Jap BK (2001) Structural basis of water-specific transport through the AQP1 water channel. Nature 414:872–878PubMedCrossRefGoogle Scholar
  46. Tajkhorshid E, Nollert P, Jensen MØ, Miercke LJW, O'Connell J, Stroud RM, Schulten K (2002) Control of the selectivity of the aquaporin water channel family by global orientational tuning. Science 296:525–530PubMedCrossRefGoogle Scholar
  47. Törnroth-Horsefield S, Wang Y, Hedfalk K, Johanson U, Karlsson M, Tajkhorshid E, Neutze R, Kjellbom P (2006) Structural mechanism of plant aquaporin gating. Nature 439:688–694PubMedCrossRefGoogle Scholar
  48. Torrie GM, Valleau JP (1974) Monte Carlo free energy estimates using non-Boltzmann sampling: application to the sub-critical Lennard-Jones fluid. Chem Phys Lett 28:578–581CrossRefGoogle Scholar
  49. Uehlein N, Lovisolo C, Siefritz F, Kaldenhoff R (2003) The tobacco aquaporin NtAQP1 is a membrane CO2 pore with physiological functions. Nature 425:734–737PubMedCrossRefGoogle Scholar
  50. Wang Y, Schulten K, Tajkhorshid E (2005) What makes an aquaporin a glycerol channel? A comparative study of AqpZ and GlpF. Structure 13:1107–1118PubMedCrossRefGoogle Scholar
  51. Wang Y, Cohen J, Boron WF, Schulten K, Tajkhorshid E (2007) Exploring gas permeability of cellular membranes and membrane channels with molecular dynamics. J Struct Biol 157: 534–544PubMedCrossRefGoogle Scholar
  52. Yang B, Fukuda N, van Hoek A, Matthay MA, Ma T, Verkman AS (2000) Carbon dioxide permeability of aquaporin-1 measured in erythrocytes and lung of aquaporin-1 null mice and in reconstituted proteoliposomes. J Biol Chem 275:2686–2692PubMedCrossRefGoogle Scholar
  53. Zardoya R (2005) Phylogeny and evolution of the major intrinsic protein family. Biol Cell 97: 397–414PubMedCrossRefGoogle Scholar
  54. Zeidel ML, Ambudkar SV, Smith BL, Agre P (1992) Reconstitution of functional water channels in liposomes containing purified red-cell CHIP28 protein. Biochemistry 31:7436–7440PubMedCrossRefGoogle Scholar
  55. Zeidel ML, Nielsen S, Smith BL, Ambudkar SV, Maunsbach AB, Agre P (1994) Ultrastructure, pharmacological inhibition, and transport selectivity of aquaporin channel-forming integral protein in proteoliposomes. Biochemistry 33:1606–1615PubMedCrossRefGoogle Scholar
  56. Zhu F, Tajkhorshid E, Schulten K (2002) Pressure-induced water transport in membrane channels studied by molecular dynamics. Biophys J 83:154–160PubMedGoogle Scholar
  57. Zhu F, Tajkhorshid E, Schulten K (2004a) Collective diffusion model for water permeation through microscopic channels. Phys Rev Lett 93:224501CrossRefGoogle Scholar
  58. Zhu F, Tajkhorshid E, Schulten K (2004b) Theory and simulation of water permeation in aquaporin-1. Biophys J 86:50–57Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Jochen S. Hub
    • 1
  • Helmut Grubmüller
    • 2
  • Bert L. de Groot
    • 1
    Email author
  1. 1.Computational Biomolecular Dynamics GroupMax-Planck-Institute for Biophysical ChemistryGöttingenGermany
  2. 2.Department of Theoretical and Computational BiophysicsMax-Planck-Institute for Biophysical ChemistryGöttingenGermany

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