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Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter

Multiscale modeling provides a very powerful means of studying complex biological systems. An important component of this strategy involves coarse-grained (CG) simplifications of regions of the system, which allow effective exploration of complex systems. Here we studied aspects of CG modeling of th...

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Autores principales: Golan, Yarden, Alhadeff, Raphael, Glaser, Fabian, Ganoth, Assaf, Warshel, Arieh, Assaraf, Yehuda G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241132/
https://www.ncbi.nlm.nih.gov/pubmed/30388104
http://dx.doi.org/10.1371/journal.pcbi.1006503
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author Golan, Yarden
Alhadeff, Raphael
Glaser, Fabian
Ganoth, Assaf
Warshel, Arieh
Assaraf, Yehuda G.
author_facet Golan, Yarden
Alhadeff, Raphael
Glaser, Fabian
Ganoth, Assaf
Warshel, Arieh
Assaraf, Yehuda G.
author_sort Golan, Yarden
collection PubMed
description Multiscale modeling provides a very powerful means of studying complex biological systems. An important component of this strategy involves coarse-grained (CG) simplifications of regions of the system, which allow effective exploration of complex systems. Here we studied aspects of CG modeling of the human zinc transporter ZnT2. Zinc is an essential trace element with 10% of the proteins in the human proteome capable of zinc binding. Thus, zinc deficiency or impairment of zinc homeostasis disrupt key cellular functions. Mammalian zinc transport proceeds via two transporter families: ZnT and ZIP; however, little is known about the zinc permeation pathway through these transporters. As a step towards this end, we herein undertook comprehensive computational analyses employing multiscale techniques, focusing on the human zinc transporter ZnT2 and its bacterial homologue, YiiP. Energy calculations revealed a favorable pathway for zinc translocation via alternating access. We then identified key residues presumably involved in the passage of zinc ions through ZnT2 and YiiP, and functionally validated their role in zinc transport using site-directed mutagenesis of ZnT2 residues. Finally, we use a CG Monte Carlo simulation approach to sample the transition between the inward-facing and the outward-facing states. We present our structural models of the inward- and outward-facing conformations of ZnT2 as a blueprint prototype of the transporter conformations, including the putative permeation pathway and participating residues. The insights gained from this study may facilitate the delineation of the pathways of other zinc transporters, laying the foundations for the molecular basis underlying ion permeation. This may possibly facilitate the development of therapeutic interventions in pathological states associated with zinc deficiency and other disorders based on loss-of-function mutations in solute carriers.
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spelling pubmed-62411322018-12-06 Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter Golan, Yarden Alhadeff, Raphael Glaser, Fabian Ganoth, Assaf Warshel, Arieh Assaraf, Yehuda G. PLoS Comput Biol Research Article Multiscale modeling provides a very powerful means of studying complex biological systems. An important component of this strategy involves coarse-grained (CG) simplifications of regions of the system, which allow effective exploration of complex systems. Here we studied aspects of CG modeling of the human zinc transporter ZnT2. Zinc is an essential trace element with 10% of the proteins in the human proteome capable of zinc binding. Thus, zinc deficiency or impairment of zinc homeostasis disrupt key cellular functions. Mammalian zinc transport proceeds via two transporter families: ZnT and ZIP; however, little is known about the zinc permeation pathway through these transporters. As a step towards this end, we herein undertook comprehensive computational analyses employing multiscale techniques, focusing on the human zinc transporter ZnT2 and its bacterial homologue, YiiP. Energy calculations revealed a favorable pathway for zinc translocation via alternating access. We then identified key residues presumably involved in the passage of zinc ions through ZnT2 and YiiP, and functionally validated their role in zinc transport using site-directed mutagenesis of ZnT2 residues. Finally, we use a CG Monte Carlo simulation approach to sample the transition between the inward-facing and the outward-facing states. We present our structural models of the inward- and outward-facing conformations of ZnT2 as a blueprint prototype of the transporter conformations, including the putative permeation pathway and participating residues. The insights gained from this study may facilitate the delineation of the pathways of other zinc transporters, laying the foundations for the molecular basis underlying ion permeation. This may possibly facilitate the development of therapeutic interventions in pathological states associated with zinc deficiency and other disorders based on loss-of-function mutations in solute carriers. Public Library of Science 2018-11-02 /pmc/articles/PMC6241132/ /pubmed/30388104 http://dx.doi.org/10.1371/journal.pcbi.1006503 Text en © 2018 Golan et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Golan, Yarden
Alhadeff, Raphael
Glaser, Fabian
Ganoth, Assaf
Warshel, Arieh
Assaraf, Yehuda G.
Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title_full Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title_fullStr Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title_full_unstemmed Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title_short Demonstrating aspects of multiscale modeling by studying the permeation pathway of the human ZnT2 zinc transporter
title_sort demonstrating aspects of multiscale modeling by studying the permeation pathway of the human znt2 zinc transporter
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241132/
https://www.ncbi.nlm.nih.gov/pubmed/30388104
http://dx.doi.org/10.1371/journal.pcbi.1006503
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