Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1

Hui Li, Hanning Chen, Christina Steinbronn, Binghua Wu, Eric Beitz, Thomas Zeuthen, Gregory A Voth

Research output: Contribution to journalJournal articleResearchpeer-review

60 Citations (Scopus)

Abstract

Prevention of cation permeation in wild-type aquaporin-1 (AQP1) is believed to be associated with the Asn-Pro-Ala (NPA) region and the aromatic/arginine selectivity filter (SF) domain. Previous work has suggested that the NPA region helps to impede proton permeation due to the protein backbone collective macrodipoles that create an environment favoring a directionally discontinuous channel hydrogen-bonded water chain and a large electrostatic barrier. The SF domain contributes to the proton permeation barrier by a spatial restriction mechanism and direct electrostatic interactions. To further explore these various effects, the free-energy barriers and the maximum cation conductance for the permeation of various cations through the AQP1-R195V and AQP1-R195S mutants are predicted computationally. The cations studied included the hydrated excess proton that utilizes the Grotthuss shuttling mechanism, a model "classical" charge localized hydronium cation that exhibits no Grotthuss shuttling, and a sodium cation. The hydrated excess proton was simulated using a specialized multi-state molecular dynamics method including a proper physical treatment of the proton shuttling and charge defect delocalization. Both AQP1 mutants exhibit a surprising cooperative effect leading to a reduction in the free-energy barrier for proton permeation around the NPA region due to altered water configurations in the SF region, with AQP1-R195S having a higher conductance than AQP1-R195V. The theoretical predictions are experimentally confirmed in wild-type AQP1 and the mutants expressed in Xenopus oocytes. The combined results suggest that the SF domain is a specialized structure that has evolved to impede proton permeation in aquaporins.
Original languageEnglish
JournalJournal of Molecular Biology
Volume407
Issue number4
Pages (from-to)607-20
Number of pages14
ISSN1089-8638
DOIs
Publication statusPublished - 8 Apr 2011

Keywords

  • Animals
  • Aquaporin 1
  • Cations
  • Cloning, Molecular
  • Computational Biology
  • Computer Simulation
  • Gene Expression
  • Models, Molecular
  • Mutant Proteins
  • Mutation, Missense
  • Oocytes
  • Protein Structure, Tertiary
  • Protons
  • Static Electricity
  • Xenopus

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