The impact of a ligand binding on strand migration in the SAM-I riboswitch
Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches larg...
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| creator | Huang, Wei Kim, Joohyun Jha, Shantenu Aboul-ela, Fareed |
| description | Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule ( |
| doi_str_mv | 10.1371/journal.pcbi.1003069 |
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Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally.</description><identifier>ISSN: 1553-7358</identifier><identifier>ISSN: 1553-734X</identifier><identifier>EISSN: 1553-7358</identifier><identifier>DOI: 10.1371/journal.pcbi.1003069</identifier><identifier>PMID: 23704854</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Biology ; Chemistry ; Cluster Analysis ; Computational Biology - methods ; Gene expression ; Hydrogen Bonding ; Ligands ; Ligands (Biochemistry) ; Metabolites ; Migration ; Models, Genetic ; Molecular Dynamics Simulation ; Molecular genetics ; Nucleic Acid Conformation ; Physiological aspects ; Protein binding ; Proteins ; Riboswitch - genetics ; RNA sequencing ; RNA, Bacterial - chemistry ; RNA, Bacterial - genetics ; RNA, Bacterial - metabolism ; S-Adenosylmethionine - chemistry ; S-Adenosylmethionine - genetics ; S-Adenosylmethionine - metabolism ; Simulation</subject><ispartof>PLoS computational biology, 2013-05, Vol.9 (5), p.e1003069-e1003069</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Huang et al 2013 Huang et al</rights><rights>2013 Huang et al. 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 credited: Huang W, Kim J, Jha S, Aboul-ela F (2013) The Impact of a Ligand Binding on Strand Migration in the SAM-I Riboswitch. 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Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally.</description><subject>Biology</subject><subject>Chemistry</subject><subject>Cluster Analysis</subject><subject>Computational Biology - methods</subject><subject>Gene expression</subject><subject>Hydrogen Bonding</subject><subject>Ligands</subject><subject>Ligands (Biochemistry)</subject><subject>Metabolites</subject><subject>Migration</subject><subject>Models, Genetic</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular genetics</subject><subject>Nucleic Acid Conformation</subject><subject>Physiological aspects</subject><subject>Protein binding</subject><subject>Proteins</subject><subject>Riboswitch - genetics</subject><subject>RNA sequencing</subject><subject>RNA, Bacterial - chemistry</subject><subject>RNA, Bacterial - genetics</subject><subject>RNA, Bacterial - metabolism</subject><subject>S-Adenosylmethionine - chemistry</subject><subject>S-Adenosylmethionine - genetics</subject><subject>S-Adenosylmethionine - metabolism</subject><subject>Simulation</subject><issn>1553-7358</issn><issn>1553-734X</issn><issn>1553-7358</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>DOA</sourceid><recordid>eNqVkkuPFCEUhStG44yj_8BoLXXRLRTP2ph0Jj7ajJo445pcKKqaThW0QPv499J2zWR6aUiAXL5zgJNbVc8xWmIi8Jtt2EcP43JntFtihAji7YPqHDNGFoIw-fDe_qx6ktK2MEy2_HF11hCBqGT0vPp0s7G1m3Zgch36GurRDeC7WjvfOT_Uwdcpx0NlckOE7ErB-ToX1fXq82JdR6dD-uWy2TytHvUwJvtsXi-q7-_f3Vx-XFx9_bC-XF0tDEcslxmERlKwFneEAW0pI6bvgQvUaMqhEZjIjkuCbMsF4xyAaEobQ6AjoAW5qF4efXdjSGqOISlMuOSYcYIKsT4SXYCt2kU3QfyjAjj1rxDioCBmZ0araImEaiE1bVuqrYVedL0g5VKNW9J0xevtfNteT7Yz1pc4xhPT0xPvNmoIPxXhjKO2LQavZoMYfuxtympyydhxBG_D_vBuxqjEUtCCLo_oAOVpzvehOJoyOjs5E7ztXamvCKGN4BLjInh9IihMtr_zAPuU1Pr623-wX05ZemRNDClF29_9FyN16L7b2NWh-9TcfUX24n5Wd6LbdiN_ARP71QA</recordid><startdate>20130501</startdate><enddate>20130501</enddate><creator>Huang, Wei</creator><creator>Kim, Joohyun</creator><creator>Jha, Shantenu</creator><creator>Aboul-ela, Fareed</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>ISN</scope><scope>ISR</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130501</creationdate><title>The impact of a ligand binding on strand migration in the SAM-I riboswitch</title><author>Huang, Wei ; Kim, Joohyun ; Jha, Shantenu ; Aboul-ela, Fareed</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c605t-c6a7b087591d35a49453cffa6702b46a27138d6830e967566aa3b442c3ad3ab73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Biology</topic><topic>Chemistry</topic><topic>Cluster Analysis</topic><topic>Computational Biology - methods</topic><topic>Gene expression</topic><topic>Hydrogen Bonding</topic><topic>Ligands</topic><topic>Ligands (Biochemistry)</topic><topic>Metabolites</topic><topic>Migration</topic><topic>Models, Genetic</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular genetics</topic><topic>Nucleic Acid Conformation</topic><topic>Physiological aspects</topic><topic>Protein binding</topic><topic>Proteins</topic><topic>Riboswitch - genetics</topic><topic>RNA sequencing</topic><topic>RNA, Bacterial - chemistry</topic><topic>RNA, Bacterial - genetics</topic><topic>RNA, Bacterial - metabolism</topic><topic>S-Adenosylmethionine - chemistry</topic><topic>S-Adenosylmethionine - genetics</topic><topic>S-Adenosylmethionine - metabolism</topic><topic>Simulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Wei</creatorcontrib><creatorcontrib>Kim, Joohyun</creatorcontrib><creatorcontrib>Jha, Shantenu</creatorcontrib><creatorcontrib>Aboul-ela, Fareed</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Canada</collection><collection>Gale In Context: Science</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS computational biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Huang, Wei</au><au>Kim, Joohyun</au><au>Jha, Shantenu</au><au>Aboul-ela, Fareed</au><au>MacKerell, Alexander Donald</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The impact of a ligand binding on strand migration in the SAM-I riboswitch</atitle><jtitle>PLoS computational biology</jtitle><addtitle>PLoS Comput Biol</addtitle><date>2013-05-01</date><risdate>2013</risdate><volume>9</volume><issue>5</issue><spage>e1003069</spage><epage>e1003069</epage><pages>e1003069-e1003069</pages><issn>1553-7358</issn><issn>1553-734X</issn><eissn>1553-7358</eissn><abstract>Riboswitches sense cellular concentrations of small molecules and use this information to adjust synthesis rates of related metabolites. Riboswitches include an aptamer domain to detect the ligand and an expression platform to control gene expression. Previous structural studies of riboswitches largely focused on aptamers, truncating the expression domain to suppress conformational switching. To link ligand/aptamer binding to conformational switching, we constructed models of an S-adenosyl methionine (SAM)-I riboswitch RNA segment incorporating elements of the expression platform, allowing formation of an antiterminator (AT) helix. Using Anton, a computer specially developed for long timescale Molecular Dynamics (MD), we simulated an extended (three microseconds) MD trajectory with SAM bound to a modeled riboswitch RNA segment. Remarkably, we observed a strand migration, converting three base pairs from an antiterminator (AT) helix, characteristic of the transcription ON state, to a P1 helix, characteristic of the OFF state. This conformational switching towards the OFF state is observed only in the presence of SAM. Among seven extended trajectories with three starting structures, the presence of SAM enhances the trend towards the OFF state for two out of three starting structures tested. Our simulation provides a visual demonstration of how a small molecule (<500 MW) binding to a limited surface can trigger a large scale conformational rearrangement in a 40 kDa RNA by perturbing the Free Energy Landscape. Such a mechanism can explain minimal requirements for SAM binding and transcription termination for SAM-I riboswitches previously reported experimentally.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23704854</pmid><doi>10.1371/journal.pcbi.1003069</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Biology Chemistry Cluster Analysis Computational Biology - methods Gene expression Hydrogen Bonding Ligands Ligands (Biochemistry) Metabolites Migration Models, Genetic Molecular Dynamics Simulation Molecular genetics Nucleic Acid Conformation Physiological aspects Protein binding Proteins Riboswitch - genetics RNA sequencing RNA, Bacterial - chemistry RNA, Bacterial - genetics RNA, Bacterial - metabolism S-Adenosylmethionine - chemistry S-Adenosylmethionine - genetics S-Adenosylmethionine - metabolism Simulation |
| title | The impact of a ligand binding on strand migration in the SAM-I riboswitch |
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