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Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme

[Image: see text] Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO(2) into bicarbonate (HCO(3)(–)) and a proton (H(+)) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as contr...

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Autores principales: Ma, Huishu, Li, Anbang, Gao, Kaifu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2017
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045336/
https://www.ncbi.nlm.nih.gov/pubmed/30023582
http://dx.doi.org/10.1021/acsomega.7b01414
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author Ma, Huishu
Li, Anbang
Gao, Kaifu
author_facet Ma, Huishu
Li, Anbang
Gao, Kaifu
author_sort Ma, Huishu
collection PubMed
description [Image: see text] Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO(2) into bicarbonate (HCO(3)(–)) and a proton (H(+)) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as controlling the pH level in cells and so on. However, the binding mechanism between apo-HCA II and CO(2) or other ligands as well as related conformational changes remains poorly understood, and atomic investigation into it could promote our understanding of related internal physiological/pathological mechanisms. In this study, long-time atomic molecular dynamics simulations as well as the clustering and free-energy analysis were performed to reveal the dynamics of apo-HCA II as well as the mechanism upon ligand binding. Our simulations indicate that the crystallographic B-factors considerably underestimate the loop dynamics: multiple conformations can be adopted by loops 1 and 2, especially for loop 1 because loop 1 is one side of the binding pocket, and its left-to-right movement can compress or extend the binding pocket, leading to one inactive (closed) state, three intermediate (semiopen) states, and one active (open) state; CO(2) cannot get into the binding pocket of the inactive state but can get into those of intermediate and active states. The coexistence of multiple conformational states proposes a possible conformational selection model for the binding mechanism between apo-HCA II and CO(2) or other ligands, revising our previous view of its functional mechanism of conformational change upon ligand binding and offering valuable structural insights into the workings of HCA II.
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spelling pubmed-60453362018-07-16 Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme Ma, Huishu Li, Anbang Gao, Kaifu ACS Omega [Image: see text] Human carbonic anhydrase II (HCA II) is an enzyme that catalyzes the reversible hydration of CO(2) into bicarbonate (HCO(3)(–)) and a proton (H(+)) as well as other reactions at an extremely high rate. This enzyme plays fundamental roles in human physiology/pathology, such as controlling the pH level in cells and so on. However, the binding mechanism between apo-HCA II and CO(2) or other ligands as well as related conformational changes remains poorly understood, and atomic investigation into it could promote our understanding of related internal physiological/pathological mechanisms. In this study, long-time atomic molecular dynamics simulations as well as the clustering and free-energy analysis were performed to reveal the dynamics of apo-HCA II as well as the mechanism upon ligand binding. Our simulations indicate that the crystallographic B-factors considerably underestimate the loop dynamics: multiple conformations can be adopted by loops 1 and 2, especially for loop 1 because loop 1 is one side of the binding pocket, and its left-to-right movement can compress or extend the binding pocket, leading to one inactive (closed) state, three intermediate (semiopen) states, and one active (open) state; CO(2) cannot get into the binding pocket of the inactive state but can get into those of intermediate and active states. The coexistence of multiple conformational states proposes a possible conformational selection model for the binding mechanism between apo-HCA II and CO(2) or other ligands, revising our previous view of its functional mechanism of conformational change upon ligand binding and offering valuable structural insights into the workings of HCA II. American Chemical Society 2017-11-29 /pmc/articles/PMC6045336/ /pubmed/30023582 http://dx.doi.org/10.1021/acsomega.7b01414 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Ma, Huishu
Li, Anbang
Gao, Kaifu
Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title_full Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title_fullStr Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title_full_unstemmed Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title_short Network of Conformational Transitions Revealed by Molecular Dynamics Simulations of the Carbonic Anhydrase II Apo-Enzyme
title_sort network of conformational transitions revealed by molecular dynamics simulations of the carbonic anhydrase ii apo-enzyme
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045336/
https://www.ncbi.nlm.nih.gov/pubmed/30023582
http://dx.doi.org/10.1021/acsomega.7b01414
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