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Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins
Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes s...
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| Published in: | Nucleic acids research 2019-07, Vol.47 (13), p.7130-7142 |
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| Main Authors: | , , , , , , , , , , |
| Format: | Article |
| Language: | English |
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| container_end_page | 7142 |
| container_issue | 13 |
| container_start_page | 7130 |
| container_title | Nucleic acids research |
| container_volume | 47 |
| creator | Vanmeert, Michiel Razzokov, Jamoliddin Mirza, Muhammad Usman Weeks, Stephen D Schepers, Guy Bogaerts, Annemie Rozenski, Jef Froeyen, Mathy Herdewijn, Piet Pinheiro, Vitor B Lescrinier, Eveline |
| description | Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase. |
| doi_str_mv | 10.1093/nar/gkz551 |
| format | article |
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In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkz551</identifier><identifier>PMID: 31334814</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Computer Simulation ; Deoxyribonuclease BamHI - metabolism ; DNA Ligases - chemistry ; DNA Ligases - metabolism ; DNA Viruses - enzymology ; DNA, Viral - metabolism ; Models, Chemical ; Molecular Docking Simulation ; Mutagenesis, Site-Directed ; Nucleic Acid Conformation ; Protein Binding ; Protein Conformation ; Structure-Activity Relationship ; Substrate Specificity ; Synthetic Biology and Bioengineering ; Templates, Genetic ; Viral Proteins - chemistry ; Viral Proteins - metabolism</subject><ispartof>Nucleic acids research, 2019-07, Vol.47 (13), p.7130-7142</ispartof><rights>The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. 2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c444t-94be6608bdabea13427ce576f16f76c6c9abf29370a617a7b6f02e1a4dbbc6f03</citedby><cites>FETCH-LOGICAL-c444t-94be6608bdabea13427ce576f16f76c6c9abf29370a617a7b6f02e1a4dbbc6f03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649754/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649754/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,733,786,790,891,27957,27958,53827,53829</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31334814$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vanmeert, Michiel</creatorcontrib><creatorcontrib>Razzokov, Jamoliddin</creatorcontrib><creatorcontrib>Mirza, Muhammad Usman</creatorcontrib><creatorcontrib>Weeks, Stephen D</creatorcontrib><creatorcontrib>Schepers, Guy</creatorcontrib><creatorcontrib>Bogaerts, Annemie</creatorcontrib><creatorcontrib>Rozenski, Jef</creatorcontrib><creatorcontrib>Froeyen, Mathy</creatorcontrib><creatorcontrib>Herdewijn, Piet</creatorcontrib><creatorcontrib>Pinheiro, Vitor B</creatorcontrib><creatorcontrib>Lescrinier, Eveline</creatorcontrib><title>Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Xenobiotic nucleic acids (XNA) are nucleic acid analogues not present in nature that can be used for the storage of genetic information. In vivo XNA applications could be developed into novel biocontainment strategies, but are currently limited by the challenge of developing XNA processing enzymes such as polymerases, ligases and nucleases. Here, we present a structure-guided modelling-based strategy for the rational design of those enzymes essential for the development of XNA molecular biology. Docking of protein domains to unbound double-stranded nucleic acids is used to generate a first approximation of the extensive interaction of nucleic acid processing enzymes with their substrate. Molecular dynamics is used to optimise that prediction allowing, for the first time, the accurate prediction of how proteins that form toroidal complexes with nucleic acids interact with their substrate. Using the Chlorella virus DNA ligase as a proof of principle, we recapitulate the ligase's substrate specificity and successfully predict how to convert it into an XNA-templated XNA ligase.</description><subject>Computer Simulation</subject><subject>Deoxyribonuclease BamHI - metabolism</subject><subject>DNA Ligases - chemistry</subject><subject>DNA Ligases - metabolism</subject><subject>DNA Viruses - enzymology</subject><subject>DNA, Viral - metabolism</subject><subject>Models, Chemical</subject><subject>Molecular Docking Simulation</subject><subject>Mutagenesis, Site-Directed</subject><subject>Nucleic Acid Conformation</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Structure-Activity Relationship</subject><subject>Substrate Specificity</subject><subject>Synthetic Biology and Bioengineering</subject><subject>Templates, Genetic</subject><subject>Viral Proteins - chemistry</subject><subject>Viral Proteins - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><recordid>eNpVkNtKAzEQhoMoth5ufADJtbA22WSz3RtBxBMUBVHwyjA57DZ2m5RkV9Cnd0u1KAzMwPzzDXwInVByTknFJh7ipFl8FQXdQWPKRJ7xSuS7aEwYKTJK-HSEDlJ6J4RyWvB9NGKUMT6lfIzenqBzwUOLjU2u8TjUGDx-fbjErWsgWdzNY-ibOTZBL5xv1oHeq9B7g32vW-s0Bu1Mwl0YKgZnBtgqhs46n47QXg1tssc__RC93Fw_X91ls8fb-6vLWaY5511WcWWFIFNlQFmgjOeltkUpairqUmihK1B1XrGSgKAllErUJLcUuFFKDzM7RBcb7qpXS2u09V2EVq6iW0L8lAGc_L_xbi6b8CGF4FVZ8AFwtgHoGFKKtt7eUiLXluVgWW4sD-HTv9-20V-t7BsvDXxa</recordid><startdate>20190726</startdate><enddate>20190726</enddate><creator>Vanmeert, Michiel</creator><creator>Razzokov, Jamoliddin</creator><creator>Mirza, Muhammad Usman</creator><creator>Weeks, Stephen D</creator><creator>Schepers, Guy</creator><creator>Bogaerts, Annemie</creator><creator>Rozenski, Jef</creator><creator>Froeyen, Mathy</creator><creator>Herdewijn, Piet</creator><creator>Pinheiro, Vitor B</creator><creator>Lescrinier, Eveline</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20190726</creationdate><title>Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins</title><author>Vanmeert, Michiel ; 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| ispartof | Nucleic acids research, 2019-07, Vol.47 (13), p.7130-7142 |
| issn | 0305-1048 1362-4962 |
| language | eng |
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| source | PubMed Central (Open access); Oxford Journals Online |
| subjects | Computer Simulation Deoxyribonuclease BamHI - metabolism DNA Ligases - chemistry DNA Ligases - metabolism DNA Viruses - enzymology DNA, Viral - metabolism Models, Chemical Molecular Docking Simulation Mutagenesis, Site-Directed Nucleic Acid Conformation Protein Binding Protein Conformation Structure-Activity Relationship Substrate Specificity Synthetic Biology and Bioengineering Templates, Genetic Viral Proteins - chemistry Viral Proteins - metabolism |
| title | Rational design of an XNA ligase through docking of unbound nucleic acids to toroidal proteins |
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