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Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR

Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the...

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Autores principales: Hu, Zengjian, Bowen, Donnell, Southerland, William M, del Sol, Antonio, Pan, Yongping, Nussinov, Ruth, Ma, Buyong
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892607/
https://www.ncbi.nlm.nih.gov/pubmed/17571919
http://dx.doi.org/10.1371/journal.pcbi.0030117
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author Hu, Zengjian
Bowen, Donnell
Southerland, William M
del Sol, Antonio
Pan, Yongping
Nussinov, Ruth
Ma, Buyong
author_facet Hu, Zengjian
Bowen, Donnell
Southerland, William M
del Sol, Antonio
Pan, Yongping
Nussinov, Ruth
Ma, Buyong
author_sort Hu, Zengjian
collection PubMed
description Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has “network-bridging effects” on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness.
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spelling pubmed-18926072007-06-30 Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR Hu, Zengjian Bowen, Donnell Southerland, William M del Sol, Antonio Pan, Yongping Nussinov, Ruth Ma, Buyong PLoS Comput Biol Research Article Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase (DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has “network-bridging effects” on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness. Public Library of Science 2007-06 2007-06-15 /pmc/articles/PMC1892607/ /pubmed/17571919 http://dx.doi.org/10.1371/journal.pcbi.0030117 Text en This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Hu, Zengjian
Bowen, Donnell
Southerland, William M
del Sol, Antonio
Pan, Yongping
Nussinov, Ruth
Ma, Buyong
Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title_full Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title_fullStr Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title_full_unstemmed Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title_short Ligand Binding and Circular Permutation Modify Residue Interaction Network in DHFR
title_sort ligand binding and circular permutation modify residue interaction network in dhfr
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1892607/
https://www.ncbi.nlm.nih.gov/pubmed/17571919
http://dx.doi.org/10.1371/journal.pcbi.0030117
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