Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1
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Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1. / Li, Hui; Chen, Hanning; Steinbronn, Christina; Wu, Binghua; Beitz, Eric; Zeuthen, Thomas; Voth, Gregory A.
I: Journal of Molecular Biology, Bind 407, Nr. 4, 08.04.2011, s. 607-20.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Enhancement of proton conductance by mutations of the selectivity filter of aquaporin-1
AU - Li, Hui
AU - Chen, Hanning
AU - Steinbronn, Christina
AU - Wu, Binghua
AU - Beitz, Eric
AU - Zeuthen, Thomas
AU - Voth, Gregory A
N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.
PY - 2011/4/8
Y1 - 2011/4/8
N2 - 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.
AB - 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.
KW - Animals
KW - Aquaporin 1
KW - Cations
KW - Cloning, Molecular
KW - Computational Biology
KW - Computer Simulation
KW - Gene Expression
KW - Models, Molecular
KW - Mutant Proteins
KW - Mutation, Missense
KW - Oocytes
KW - Protein Structure, Tertiary
KW - Protons
KW - Static Electricity
KW - Xenopus
U2 - 10.1016/j.jmb.2011.01.036
DO - 10.1016/j.jmb.2011.01.036
M3 - Journal article
C2 - 21277313
VL - 407
SP - 607
EP - 620
JO - Journal of Molecular Biology
JF - Journal of Molecular Biology
SN - 0022-2836
IS - 4
ER -
ID: 33543906