Frustration in protein–DNA binding influences conformational switching and target search kinetics
Rapid recognition of DNA target sites involves facilitated diffusion through which alternative sites are searched on genomic DNA. A key mechanism facilitating the localization of the target by a DNA-binding protein (DBP) is one-dimensional diffusion (sliding) in which electrostatic forces attract th...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (44), p.17957-17962 |
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| creator | Marcovitz, Amir Levy, Yaakov |
| description | Rapid recognition of DNA target sites involves facilitated diffusion through which alternative sites are searched on genomic DNA. A key mechanism facilitating the localization of the target by a DNA-binding protein (DBP) is one-dimensional diffusion (sliding) in which electrostatic forces attract the protein to the DNA. As the protein reaches its target DNA site, it switches from purely electrostatic binding to a specific set of interactions with the DNA bases that also involves hydrogen bonding and van der Waals forces. High overlap between the DBP patches used for nonspecific and specific interactions with DNA may enable an immediate transition between the two binding modes following target site localization. By contrast, an imperfect overlap may result in greater frustration between the two potentially competing binding modes and consequently slower switching between them. A structural analysis of 125 DBPs indicates frustration between the two binding modes that results in a large difference between the orientations of the protein to the DNA when it slides compared to when it specifically interacts with DNA. Coarse-grained molecular dynamics simulations of in silico designed peptides comprising the full range of frustrations between the two interfaces show slower transition from nonspecific to specific DNA binding as the overlap between the patches involved in the two binding modes decreases. The complex search kinetics may regulate the search by eliminating trapping of the protein in semispecific sites while sliding. |
| doi_str_mv | 10.1073/pnas.1109594108 |
| format | Article |
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A key mechanism facilitating the localization of the target by a DNA-binding protein (DBP) is one-dimensional diffusion (sliding) in which electrostatic forces attract the protein to the DNA. As the protein reaches its target DNA site, it switches from purely electrostatic binding to a specific set of interactions with the DNA bases that also involves hydrogen bonding and van der Waals forces. High overlap between the DBP patches used for nonspecific and specific interactions with DNA may enable an immediate transition between the two binding modes following target site localization. By contrast, an imperfect overlap may result in greater frustration between the two potentially competing binding modes and consequently slower switching between them. A structural analysis of 125 DBPs indicates frustration between the two binding modes that results in a large difference between the orientations of the protein to the DNA when it slides compared to when it specifically interacts with DNA. Coarse-grained molecular dynamics simulations of in silico designed peptides comprising the full range of frustrations between the two interfaces show slower transition from nonspecific to specific DNA binding as the overlap between the patches involved in the two binding modes decreases. The complex search kinetics may regulate the search by eliminating trapping of the protein in semispecific sites while sliding.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1109594108</identifier><identifier>PMID: 22003125</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Binding sites ; Biological Sciences ; Crystal structure ; Datasets ; Deoxyribonucleic acid ; Diffusion ; DNA ; DNA - metabolism ; DNA-binding protein ; Electrical potential ; electrostatic interactions ; Electrostatic properties ; Electrostatics ; Enzymes ; facilitated diffusion ; Frustration ; Genomics ; Hydrogen Bonding ; Kinetics ; Models, Molecular ; molecular dynamics ; Nucleotide sequences ; Protein Conformation ; Proteins ; Proteins - chemistry ; Proteins - metabolism ; Simulation ; Sliding ; Static Electricity</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-11, Vol.108 (44), p.17957-17962</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Nov 1, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-3f32b59eae368b739b2b51ac99784a49d17914725a3bc727ddc7a9f15d12553</citedby><cites>FETCH-LOGICAL-c588t-3f32b59eae368b739b2b51ac99784a49d17914725a3bc727ddc7a9f15d12553</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/44.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41352634$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41352634$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27924,27925,53791,53793,58017,58250</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22003125$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Marcovitz, Amir</creatorcontrib><creatorcontrib>Levy, Yaakov</creatorcontrib><title>Frustration in protein–DNA binding influences conformational switching and target search kinetics</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Rapid recognition of DNA target sites involves facilitated diffusion through which alternative sites are searched on genomic DNA. A key mechanism facilitating the localization of the target by a DNA-binding protein (DBP) is one-dimensional diffusion (sliding) in which electrostatic forces attract the protein to the DNA. As the protein reaches its target DNA site, it switches from purely electrostatic binding to a specific set of interactions with the DNA bases that also involves hydrogen bonding and van der Waals forces. High overlap between the DBP patches used for nonspecific and specific interactions with DNA may enable an immediate transition between the two binding modes following target site localization. By contrast, an imperfect overlap may result in greater frustration between the two potentially competing binding modes and consequently slower switching between them. A structural analysis of 125 DBPs indicates frustration between the two binding modes that results in a large difference between the orientations of the protein to the DNA when it slides compared to when it specifically interacts with DNA. Coarse-grained molecular dynamics simulations of in silico designed peptides comprising the full range of frustrations between the two interfaces show slower transition from nonspecific to specific DNA binding as the overlap between the patches involved in the two binding modes decreases. The complex search kinetics may regulate the search by eliminating trapping of the protein in semispecific sites while sliding.</description><subject>Binding sites</subject><subject>Biological Sciences</subject><subject>Crystal structure</subject><subject>Datasets</subject><subject>Deoxyribonucleic acid</subject><subject>Diffusion</subject><subject>DNA</subject><subject>DNA - metabolism</subject><subject>DNA-binding protein</subject><subject>Electrical potential</subject><subject>electrostatic interactions</subject><subject>Electrostatic properties</subject><subject>Electrostatics</subject><subject>Enzymes</subject><subject>facilitated diffusion</subject><subject>Frustration</subject><subject>Genomics</subject><subject>Hydrogen Bonding</subject><subject>Kinetics</subject><subject>Models, Molecular</subject><subject>molecular dynamics</subject><subject>Nucleotide sequences</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Proteins - chemistry</subject><subject>Proteins - metabolism</subject><subject>Simulation</subject><subject>Sliding</subject><subject>Static Electricity</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAUhS0EokNhzQqIumGV1r-xvUGq-gOVKlgU1pbjODMeMvbUdkDseIe-IU-CMzOdAhtWcXS_e3TPOQC8RPAYQU5O1l6nY4SgZJIiKB6BWXmjuqESPgYzCDGvBcX0ADxLaQlh4QR8Cg4whpAgzGbAXMYx5aizC75yvlrHkK3zv37enX88rVrnO-fnZdAPo_XGpsoE34e42izooUrfXTaLidG-q7KOc5urZHU0i-qr8zY7k56DJ70ekn2x-x6Cm8uLz2cf6utP76_OTq9rw4TINekJbpm02pJGtJzItvwibaTkgmoqO8QlohwzTVrDMe86w7XsEeuKE0YOwbut6npsV7Yz1hdbg1pHt9Lxhwraqb8n3i3UPHxTBEPeiEng7U4ghtvRpqxWLhk7DNrbMCYlcSNEyZD8n4QYCsEJLeTRP-QyjLEEt4FYMcNwgU62kIkhpWj7_dEIqqlmNdWsHmouG6__9Lrn73stQLUDps0HOaEoVSVHxgvyaossUw5xz1BEGG42p7_ZznsdlJ5Hl9SXGwwRLRE0stxOfgM6j8Ma</recordid><startdate>20111101</startdate><enddate>20111101</enddate><creator>Marcovitz, Amir</creator><creator>Levy, Yaakov</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20111101</creationdate><title>Frustration in protein–DNA binding influences conformational switching and target search kinetics</title><author>Marcovitz, Amir ; Levy, Yaakov</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c588t-3f32b59eae368b739b2b51ac99784a49d17914725a3bc727ddc7a9f15d12553</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Binding sites</topic><topic>Biological Sciences</topic><topic>Crystal structure</topic><topic>Datasets</topic><topic>Deoxyribonucleic acid</topic><topic>Diffusion</topic><topic>DNA</topic><topic>DNA - metabolism</topic><topic>DNA-binding protein</topic><topic>Electrical potential</topic><topic>electrostatic interactions</topic><topic>Electrostatic properties</topic><topic>Electrostatics</topic><topic>Enzymes</topic><topic>facilitated diffusion</topic><topic>Frustration</topic><topic>Genomics</topic><topic>Hydrogen Bonding</topic><topic>Kinetics</topic><topic>Models, Molecular</topic><topic>molecular dynamics</topic><topic>Nucleotide sequences</topic><topic>Protein Conformation</topic><topic>Proteins</topic><topic>Proteins - chemistry</topic><topic>Proteins - metabolism</topic><topic>Simulation</topic><topic>Sliding</topic><topic>Static Electricity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Marcovitz, Amir</creatorcontrib><creatorcontrib>Levy, Yaakov</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Marcovitz, Amir</au><au>Levy, Yaakov</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Frustration in protein–DNA binding influences conformational switching and target search kinetics</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-11-01</date><risdate>2011</risdate><volume>108</volume><issue>44</issue><spage>17957</spage><epage>17962</epage><pages>17957-17962</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Rapid recognition of DNA target sites involves facilitated diffusion through which alternative sites are searched on genomic DNA. A key mechanism facilitating the localization of the target by a DNA-binding protein (DBP) is one-dimensional diffusion (sliding) in which electrostatic forces attract the protein to the DNA. As the protein reaches its target DNA site, it switches from purely electrostatic binding to a specific set of interactions with the DNA bases that also involves hydrogen bonding and van der Waals forces. High overlap between the DBP patches used for nonspecific and specific interactions with DNA may enable an immediate transition between the two binding modes following target site localization. By contrast, an imperfect overlap may result in greater frustration between the two potentially competing binding modes and consequently slower switching between them. A structural analysis of 125 DBPs indicates frustration between the two binding modes that results in a large difference between the orientations of the protein to the DNA when it slides compared to when it specifically interacts with DNA. Coarse-grained molecular dynamics simulations of in silico designed peptides comprising the full range of frustrations between the two interfaces show slower transition from nonspecific to specific DNA binding as the overlap between the patches involved in the two binding modes decreases. The complex search kinetics may regulate the search by eliminating trapping of the protein in semispecific sites while sliding.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>22003125</pmid><doi>10.1073/pnas.1109594108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Binding sites Biological Sciences Crystal structure Datasets Deoxyribonucleic acid Diffusion DNA DNA - metabolism DNA-binding protein Electrical potential electrostatic interactions Electrostatic properties Electrostatics Enzymes facilitated diffusion Frustration Genomics Hydrogen Bonding Kinetics Models, Molecular molecular dynamics Nucleotide sequences Protein Conformation Proteins Proteins - chemistry Proteins - metabolism Simulation Sliding Static Electricity |
| title | Frustration in protein–DNA binding influences conformational switching and target search kinetics |
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