Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning
Identifieur interne : 000118 ( Pmc/Curation ); précédent : 000117; suivant : 000119Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning
Auteurs : Lane W. Votapka ; Rommie E. AmaroSource :
- PLoS Computational Biology [ 1553-734X ] ; 2015.
Abstract
The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the kon rate constant for superoxide dismutase with its natural substrate, O2−, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the kon for a new system: the N-terminal domain of Troponin C with its natural substrate Ca2+. The kon calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor.
Url:
DOI: 10.1371/journal.pcbi.1004381
PubMed: 26505480
PubMed Central: 4624728
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning</title><author><name sortKey="Votapka, Lane W" sort="Votapka, Lane W" uniqKey="Votapka L" first="Lane W." last="Votapka">Lane W. Votapka</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Amaro, Rommie E" sort="Amaro, Rommie E" uniqKey="Amaro R" first="Rommie E." last="Amaro">Rommie E. Amaro</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26505480</idno><idno type="pmc">4624728</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624728</idno><idno type="RBID">PMC:4624728</idno><idno type="doi">10.1371/journal.pcbi.1004381</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000118</idno><idno type="wicri:Area/Pmc/Curation">000118</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning</title><author><name sortKey="Votapka, Lane W" sort="Votapka, Lane W" uniqKey="Votapka L" first="Lane W." last="Votapka">Lane W. Votapka</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author><author><name sortKey="Amaro, Rommie E" sort="Amaro, Rommie E" uniqKey="Amaro R" first="Rommie E." last="Amaro">Rommie E. Amaro</name><affiliation><nlm:aff id="aff001"></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Computational Biology</title><idno type="ISSN">1553-734X</idno><idno type="eISSN">1553-7358</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the k<sub>on</sub> rate constant for superoxide dismutase with its natural substrate, O<sub>2</sub><sup>−</sup>, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the k<sub>on</sub> for a new system: the N-terminal domain of Troponin C with its natural substrate Ca<sup>2+</sup>. The k<sub>on</sub> calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Bar Even, A" uniqKey="Bar Even A">A Bar-Even</name></author><author><name sortKey="Noor, E" uniqKey="Noor E">E Noor</name></author><author><name sortKey="Savir, Y" uniqKey="Savir Y">Y Savir</name></author><author><name sortKey="Liebermeister, W" uniqKey="Liebermeister W">W Liebermeister</name></author><author><name sortKey="Davidi, D" uniqKey="Davidi D">D Davidi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Copeland, Ra" uniqKey="Copeland R">RA Copeland</name></author><author><name sortKey="Pompliano, Dl" uniqKey="Pompliano D">DL Pompliano</name></author><author><name sortKey="Meek, Td" uniqKey="Meek T">TD 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<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, CA USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26505480</article-id><article-id pub-id-type="pmc">4624728</article-id><article-id pub-id-type="doi">10.1371/journal.pcbi.1004381</article-id><article-id pub-id-type="publisher-id">PCOMPBIOL-D-15-00278</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group></article-categories><title-group><article-title>Multiscale Estimation of Binding Kinetics Using Brownian Dynamics, Molecular Dynamics and Milestoning</article-title><alt-title alt-title-type="running-head">Multiscale Estimation of Binding Kinetics</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Votapka</surname><given-names>Lane W.</given-names></name><xref ref-type="aff" rid="aff001"></xref></contrib><contrib contrib-type="author"><name><surname>Amaro</surname><given-names>Rommie E.</given-names></name><xref rid="cor001" ref-type="corresp">*</xref><xref ref-type="aff" rid="aff001"></xref></contrib></contrib-group><aff id="aff001"><addr-line>Department of Chemistry and Biochemistry and National Biomedical Computation Resource, University of California, San Diego, San Diego, California, United States of America</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Shehu</surname><given-names>Amarda</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>George Mason University, UNITED STATES</addr-line></aff><author-notes><fn fn-type="conflict" id="coi001"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: LWV REA. Performed the experiments: LWV. Analyzed the data: LWV. Contributed reagents/materials/analysis tools: LWV REA. Wrote the paper: LWV REA.</p></fn><corresp id="cor001">* E-mail: <email>ramaro@ucsd.edu</email></corresp></author-notes><pub-date pub-type="epub"><day>27</day><month>10</month><year>2015</year></pub-date><pub-date pub-type="collection"><month>10</month><year>2015</year></pub-date><volume>11</volume><issue>10</issue><elocation-id>e1004381</elocation-id><history><date date-type="received"><day>20</day><month>2</month><year>2015</year></date><date date-type="accepted"><day>4</day><month>6</month><year>2015</year></date></history><permissions><copyright-statement>© 2015 Votapka, Amaro</copyright-statement><copyright-year>2015</copyright-year><copyright-holder>Votapka, Amaro</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><self-uri content-type="pdf" xlink:type="simple" xlink:href="pcbi.1004381.pdf"></self-uri><abstract><p>The kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a method that uses milestoning theory to combine Brownian dynamics simulations with more detailed molecular dynamics simulations. The rate constants found using this method agreed well with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged spherical receptor and verified the estimated value with Smoluchowski theory. We also calculated the k<sub>on</sub> rate constant for superoxide dismutase with its natural substrate, O<sub>2</sub><sup>−</sup>, in a validation of a previous experiment using similar methods but with a number of important improvements. We also calculated the k<sub>on</sub> for a new system: the N-terminal domain of Troponin C with its natural substrate Ca<sup>2+</sup>. The k<sub>on</sub> calculated for the latter two systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable when compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>We estimated the k<sub>on</sub> rate constant of four biochemically relevant ligand-receptor systems using milestoning theory. All results closely resemble experimentally and theoretically determined results, indicating that this technique may be applied toward accurate estimation of binding rate constants for additional ligand-receptor systems of biomedical interest.</p></abstract><funding-group><funding-statement>This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant No. DGE-1144086. This work was funded in part by the National Institutes of Health (NIH) through the NIH Director’s New Innovator Award Program DP2-OD007237 and through the NSF XSEDE Supercomputer resources grant RAC CHE060073N to REA. Additional funding from the National Biomedical Computation Resource, NIH P41 GM103426, is gratefully acknowledged. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. 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><fig-count count="9"></fig-count><table-count count="4"></table-count><page-count count="24"></page-count></counts><custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name><meta-value>The authors confirm that all data underlying the findings are fully available without restriction. All files are available from the University of California, San Diego Research Data Curation Program. URL: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.6075/J02Z13F5">http://dx.doi.org/10.6075/J02Z13F5</ext-link>.</meta-value></custom-meta></custom-meta-group></article-meta><notes><title>Data Availability</title><p>The authors confirm that all data underlying the findings are fully available without restriction. All files are available from the University of California, San Diego Research Data Curation Program. URL: <ext-link ext-link-type="uri" xlink:href="http://dx.doi.org/10.6075/J02Z13F5">http://dx.doi.org/10.6075/J02Z13F5</ext-link>.</p></notes></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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