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Modelling the free energy profile of the mitochondrial ADP/ATP carrier

The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational chang...

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Autores principales: Springett, Roger, King, Martin S., Crichton, Paul G., Kunji, Edmund R.S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Pub. Co 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604490/
https://www.ncbi.nlm.nih.gov/pubmed/28554566
http://dx.doi.org/10.1016/j.bbabio.2017.05.006
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author Springett, Roger
King, Martin S.
Crichton, Paul G.
Kunji, Edmund R.S.
author_facet Springett, Roger
King, Martin S.
Crichton, Paul G.
Kunji, Edmund R.S.
author_sort Springett, Roger
collection PubMed
description The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational changes. These changes are prevented in the absence of substrate by a large energy barrier due to the need for sequential disruption and formation of a matrix and cytoplasmic salt bridge network that are located on either side of the central cavity. In analogy to enzyme catalysis, substrate lowers the energy barrier by binding tighter in the intermediate state. Here we provide an in-silico kinetic model that captures the free energy profile of these conformational changes and treats the carrier as a nanomachine moving stochastically from the matrix to cytoplasmic conformation under the influence of thermal energy. The model reproduces the dependency of experimentally determined k(cat) and K(M) values on the cytoplasmic network strength with good quantitative accuracy, implying that it captures the transport mechanism and can provide a framework to understand the structure-function relationships of this class of transporter. The results show that maximum transport occurs when the interaction energies of the cytoplasmic network, matrix network and substrate binding are approximately equal such that the energy barrier is minimized. Consequently, the model predicts that there will be other interactions in addition to those of the cytoplasmic network that stabilise the matrix conformation of the ADP/ATP carrier.
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spelling pubmed-56044902017-11-01 Modelling the free energy profile of the mitochondrial ADP/ATP carrier Springett, Roger King, Martin S. Crichton, Paul G. Kunji, Edmund R.S. Biochim Biophys Acta Article The mitochondrial ADP/ATP carrier catalyses the equimolar exchange of adenosine di- and tri-phosphates. It operates by an alternating access mechanism in which a single substrate-binding site is made available either to the mitochondrial matrix or the intermembrane space through conformational changes. These changes are prevented in the absence of substrate by a large energy barrier due to the need for sequential disruption and formation of a matrix and cytoplasmic salt bridge network that are located on either side of the central cavity. In analogy to enzyme catalysis, substrate lowers the energy barrier by binding tighter in the intermediate state. Here we provide an in-silico kinetic model that captures the free energy profile of these conformational changes and treats the carrier as a nanomachine moving stochastically from the matrix to cytoplasmic conformation under the influence of thermal energy. The model reproduces the dependency of experimentally determined k(cat) and K(M) values on the cytoplasmic network strength with good quantitative accuracy, implying that it captures the transport mechanism and can provide a framework to understand the structure-function relationships of this class of transporter. The results show that maximum transport occurs when the interaction energies of the cytoplasmic network, matrix network and substrate binding are approximately equal such that the energy barrier is minimized. Consequently, the model predicts that there will be other interactions in addition to those of the cytoplasmic network that stabilise the matrix conformation of the ADP/ATP carrier. Elsevier Pub. Co 2017-11 /pmc/articles/PMC5604490/ /pubmed/28554566 http://dx.doi.org/10.1016/j.bbabio.2017.05.006 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Springett, Roger
King, Martin S.
Crichton, Paul G.
Kunji, Edmund R.S.
Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title_full Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title_fullStr Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title_full_unstemmed Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title_short Modelling the free energy profile of the mitochondrial ADP/ATP carrier
title_sort modelling the free energy profile of the mitochondrial adp/atp carrier
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604490/
https://www.ncbi.nlm.nih.gov/pubmed/28554566
http://dx.doi.org/10.1016/j.bbabio.2017.05.006
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