Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function

Abstract Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and...

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Autores principales:	Viveca Lindahl, Pontus Gourdon, Magnus Andersson, Berk Hess
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/53c03b2ba91844bead5b1dffce09ba6b
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spelling	oai:doaj.org-article:53c03b2ba91844bead5b1dffce09ba6b2021-12-02T15:07:49ZPermeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function10.1038/s41598-018-21357-22045-2322https://doaj.org/article/53c03b2ba91844bead5b1dffce09ba6b2018-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-21357-2https://doaj.org/toc/2045-2322Abstract Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and explain these observations by performing an extensive mutational study using microsecond long molecular dynamics simulations, applying the two popular force fields CHARMM36 and Amber ff99SB-ILDN. We calculate permeabilities and free energies along the channel axis for ammonia and water. For one force field, the permeability of the double mutant decreases by a factor of 2.5 for water and 4 for ammonia, increasing water selectivity by a factor of 1.6. We attribute this effect to decreased entropy of water in the pore, due to the observed increase in pore–water interactions and narrower pore. Additionally, we observe spontaneous opening and closing of the pore on the cytosolic side, which suggests a gating mechanism for the pore. Our results show that sampling methods and simulation times are sufficient to delineate even subtle effects of mutations on structure and function and to capture important long-timescale events, but also underline the importance of improving models further.Viveca LindahlPontus GourdonMagnus AnderssonBerk HessNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-13 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Viveca Lindahl Pontus Gourdon Magnus Andersson Berk Hess Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
description	Abstract Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and explain these observations by performing an extensive mutational study using microsecond long molecular dynamics simulations, applying the two popular force fields CHARMM36 and Amber ff99SB-ILDN. We calculate permeabilities and free energies along the channel axis for ammonia and water. For one force field, the permeability of the double mutant decreases by a factor of 2.5 for water and 4 for ammonia, increasing water selectivity by a factor of 1.6. We attribute this effect to decreased entropy of water in the pore, due to the observed increase in pore–water interactions and narrower pore. Additionally, we observe spontaneous opening and closing of the pore on the cytosolic side, which suggests a gating mechanism for the pore. Our results show that sampling methods and simulation times are sufficient to delineate even subtle effects of mutations on structure and function and to capture important long-timescale events, but also underline the importance of improving models further.
format	article
author	Viveca Lindahl Pontus Gourdon Magnus Andersson Berk Hess
author_facet	Viveca Lindahl Pontus Gourdon Magnus Andersson Berk Hess
author_sort	Viveca Lindahl
title	Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
title_short	Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
title_full	Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
title_fullStr	Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
title_full_unstemmed	Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function
title_sort	permeability and ammonia selectivity in aquaporin tip2;1: linking structure to function
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/53c03b2ba91844bead5b1dffce09ba6b
work_keys_str_mv	AT vivecalindahl permeabilityandammoniaselectivityinaquaporintip21linkingstructuretofunction AT pontusgourdon permeabilityandammoniaselectivityinaquaporintip21linkingstructuretofunction AT magnusandersson permeabilityandammoniaselectivityinaquaporintip21linkingstructuretofunction AT berkhess permeabilityandammoniaselectivityinaquaporintip21linkingstructuretofunction
_version_	1718388384884326400

Permeability and ammonia selectivity in aquaporin TIP2;1: linking structure to function

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