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Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Identifieur interne : 001360 ( Pmc/Checkpoint ); précédent : 001359; suivant : 001361

Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model

Auteurs : Avisek Das [États-Unis] ; Mert Gur [États-Unis] ; Mary Hongying Cheng [États-Unis] ; Sunhwan Jo [États-Unis] ; Ivet Bahar [États-Unis] ; Benoît Roux [États-Unis]

Source :

RBID : PMC:3974643

Abstract

Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called ANMPathway, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that ANMPathway yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver ANMPathway results.


Url:
DOI: 10.1371/journal.pcbi.1003521
PubMed: 24699246
PubMed Central: 3974643


Affiliations:


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<name sortKey="Ahmed, A" uniqKey="Ahmed A">A Ahmed</name>
</author>
<author>
<name sortKey="Gohlke, H" uniqKey="Gohlke H">H Gohlke</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Sfriso, P" uniqKey="Sfriso P">P Sfriso</name>
</author>
<author>
<name sortKey="Emperador, A" uniqKey="Emperador A">A Emperador</name>
</author>
<author>
<name sortKey="Orellana, L" uniqKey="Orellana L">L Orellana</name>
</author>
<author>
<name sortKey="Hospital, A" uniqKey="Hospital A">A Hospital</name>
</author>
<author>
<name sortKey="Gelpi, Jl" uniqKey="Gelpi J">JL Gelpí</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="E, W" uniqKey="E W">W E</name>
</author>
<author>
<name sortKey="Ren, W" uniqKey="Ren W">W Ren</name>
</author>
<author>
<name sortKey="Vanden Eijnden, E" uniqKey="Vanden Eijnden E">E Vanden-Eijnden</name>
</author>
</analytic>
</biblStruct>
<biblStruct>
<analytic>
<author>
<name sortKey="Adelman, Jl" uniqKey="Adelman J">JL Adelman</name>
</author>
<author>
<name sortKey="Dale, Al" uniqKey="Dale A">AL Dale</name>
</author>
<author>
<name sortKey="Zwier, Mc" uniqKey="Zwier M">MC Zwier</name>
</author>
<author>
<name sortKey="Bhatt, D" uniqKey="Bhatt D">D Bhatt</name>
</author>
<author>
<name sortKey="Chong, Lt" uniqKey="Chong L">LT Chong</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article">
<pmc-dir>properties open_access</pmc-dir>
<front>
<journal-meta>
<journal-id journal-id-type="nlm-ta">PLoS Comput Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Comput. Biol</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">ploscomp</journal-id>
<journal-title-group>
<journal-title>PLoS Computational Biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-734X</issn>
<issn pub-type="epub">1553-7358</issn>
<publisher>
<publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta>
<article-id pub-id-type="pmid">24699246</article-id>
<article-id pub-id-type="pmc">3974643</article-id>
<article-id pub-id-type="publisher-id">PCOMPBIOL-D-13-01573</article-id>
<article-id pub-id-type="doi">10.1371/journal.pcbi.1003521</article-id>
<article-categories>
<subj-group subj-group-type="heading">
<subject>Research Article</subject>
</subj-group>
<subj-group subj-group-type="Discipline-v2">
<subject>Biology and Life Sciences</subject>
<subj-group>
<subject>Biophysics</subject>
</subj-group>
<subj-group>
<subject>Computational Biology</subject>
</subj-group>
</subj-group>
</article-categories>
<title-group>
<article-title>Exploring the Conformational Transitions of Biomolecular Systems Using a Simple Two-State Anisotropic Network Model</article-title>
<alt-title alt-title-type="running-head">Conformational Transitions of Biomolecular Systems</alt-title>
</title-group>
<contrib-group>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Das</surname>
<given-names>Avisek</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Gur</surname>
<given-names>Mert</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author" equal-contrib="yes">
<name>
<surname>Cheng</surname>
<given-names>Mary Hongying</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Jo</surname>
<given-names>Sunhwan</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Bahar</surname>
<given-names>Ivet</given-names>
</name>
<xref ref-type="aff" rid="aff2">
<sup>2</sup>
</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Roux</surname>
<given-names>Benoît</given-names>
</name>
<xref ref-type="aff" rid="aff1">
<sup>1</sup>
</xref>
<xref ref-type="corresp" rid="cor1">
<sup>*</sup>
</xref>
</contrib>
</contrib-group>
<aff id="aff1">
<label>1</label>
<addr-line>Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, University of Chicago, Chicago, Illinois, United States of America</addr-line>
</aff>
<aff id="aff2">
<label>2</label>
<addr-line>Department of Computational & Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America</addr-line>
</aff>
<contrib-group>
<contrib contrib-type="editor">
<name>
<surname>de Groot</surname>
<given-names>Bert L.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1">
<addr-line>Max Planck Institute for Biophysical Chemistry, Germany</addr-line>
</aff>
<author-notes>
<corresp id="cor1">* E-mail:
<email>roux@uchicago.edu</email>
</corresp>
<fn fn-type="conflict">
<p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con">
<p>Conceived and designed the experiments: AD IB BR. Performed the experiments: AD MG MHC. Analyzed the data: AD MG MHC SJ IB BR. Wrote the paper: AD MG MHC SJ IB BR.</p>
</fn>
</author-notes>
<pub-date pub-type="collection">
<month>4</month>
<year>2014</year>
</pub-date>
<pub-date pub-type="epub">
<day>3</day>
<month>4</month>
<year>2014</year>
</pub-date>
<volume>10</volume>
<issue>4</issue>
<elocation-id>e1003521</elocation-id>
<history>
<date date-type="received">
<day>3</day>
<month>9</month>
<year>2013</year>
</date>
<date date-type="accepted">
<day>1</day>
<month>2</month>
<year>2014</year>
</date>
</history>
<permissions>
<copyright-statement>© 2014 Das et al</copyright-statement>
<copyright-year>2014</copyright-year>
<copyright-holder>Das et al</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/">
<license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<abstract>
<p>Biomolecular conformational transitions are essential to biological functions. Most experimental methods report on the long-lived functional states of biomolecules, but information about the transition pathways between these stable states is generally scarce. Such transitions involve short-lived conformational states that are difficult to detect experimentally. For this reason, computational methods are needed to produce plausible hypothetical transition pathways that can then be probed experimentally. Here we propose a simple and computationally efficient method, called
<italic>ANMPathway</italic>
, for constructing a physically reasonable pathway between two endpoints of a conformational transition. We adopt a coarse-grained representation of the protein and construct a two-state potential by combining two elastic network models (ENMs) representative of the experimental structures resolved for the endpoints. The two-state potential has a cusp hypersurface in the configuration space where the energies from both the ENMs are equal. We first search for the minimum energy structure on the cusp hypersurface and then treat it as the transition state. The continuous pathway is subsequently constructed by following the steepest descent energy minimization trajectories starting from the transition state on each side of the cusp hypersurface. Application to several systems of broad biological interest such as adenylate kinase, ATP-driven calcium pump SERCA, leucine transporter and glutamate transporter shows that
<italic>ANMPathway</italic>
yields results in good agreement with those from other similar methods and with data obtained from all-atom molecular dynamics simulations, in support of the utility of this simple and efficient approach. Notably the method provides experimentally testable predictions, including the formation of non-native contacts during the transition which we were able to detect in two of the systems we studied. An open-access web server has been created to deliver
<italic>ANMPathway</italic>
results.</p>
</abstract>
<abstract abstract-type="summary">
<title>Author Summary</title>
<p>Many biomolecules are like tiny molecular machines that need to change their shapes and visit many states to perform their biological functions. For a complete molecular understanding of a biological process, one needs to have information on the relevant stable states of the system in question, as well as the pathways by which the system travels from one state to another. We report here an efficient computational method that uses the knowledge of experimental structures of a pair of stable states in order to construct an energetically favoravle pathway between them. We adopt a simple representation of the molecular system by replacing the atoms with beads connected by springs and constructing an energy function with two minima around the end-states. We searched for the structure with highest energy that the system is most likely to visit during the transition and created two paths starting from this structure and proceeding toward the end-states. The combined result of these two paths is the minimum energy pathway between the two stable states. We apply this method to study important structural changes in one enzyme and three large proteins that transport small molecules and ions across the cell membrane.</p>
</abstract>
<funding-group>
<funding-statement>This work was carried out in the context of the Membrane Protein Structural Dynamics Consortium which is funded by grant U54-GM087519 from the National Institute of Health (NIH). Additional support from NIH through grants (to I.B.) R01-GM099738, R01GM086238 and P41GM103712, and computing award from the NSF TeraGrid resources (TG-MCB130006) is gratefully acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts>
<page-count count="17"></page-count>
</counts>
</article-meta>
</front>
</pmc>
<affiliations>
<list>
<country>
<li>États-Unis</li>
</country>
<region>
<li>Illinois</li>
<li>Pennsylvanie</li>
</region>
<settlement>
<li>Pittsburgh</li>
</settlement>
<orgName>
<li>Université de Pittsburgh</li>
</orgName>
</list>
<tree>
<country name="États-Unis">
<region name="Illinois">
<name sortKey="Das, Avisek" sort="Das, Avisek" uniqKey="Das A" first="Avisek" last="Das">Avisek Das</name>
</region>
<name sortKey="Bahar, Ivet" sort="Bahar, Ivet" uniqKey="Bahar I" first="Ivet" last="Bahar">Ivet Bahar</name>
<name sortKey="Cheng, Mary Hongying" sort="Cheng, Mary Hongying" uniqKey="Cheng M" first="Mary Hongying" last="Cheng">Mary Hongying Cheng</name>
<name sortKey="Gur, Mert" sort="Gur, Mert" uniqKey="Gur M" first="Mert" last="Gur">Mert Gur</name>
<name sortKey="Jo, Sunhwan" sort="Jo, Sunhwan" uniqKey="Jo S" first="Sunhwan" last="Jo">Sunhwan Jo</name>
<name sortKey="Roux, Benoit" sort="Roux, Benoit" uniqKey="Roux B" first="Benoît" last="Roux">Benoît Roux</name>
</country>
</tree>
</affiliations>
</record>

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