Elbow Flexibility and Ligand-Induced Domain Rearrangements in Antibody Fab NC6.8: Large Effects of a Small Hapten
Four 700-ps molecular dynamics simulations were carried out to analyze the structural dynamics of the antigen-binding antibody fragment NC6.8, which is known to exhibit large structural changes upon complexation. The first simulation was started from the x-ray structure of the uncomplexed Fab and pr...
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| Veröffentlicht in: | Biophysical journal 2000-08, Vol.79 (2), p.614-628 |
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| creator | Sotriffer, Christoph A. Rode, Bernd M. Varga, Janos M. Liedl, Klaus R. |
| description | Four 700-ps molecular dynamics simulations were carried out to analyze the structural dynamics of the antigen-binding antibody fragment NC6.8, which is known to exhibit large structural changes upon complexation. The first simulation was started from the x-ray structure of the uncomplexed Fab and produced trajectory averages that closely match the crystallographic results. It allowed assessment of the flexibility of the Fab, revealing an elbow motion of the variable domains with respect to the constant domains. The second simulation was started from the uncomplexed x-ray structure after insertion of the ligand into the binding site. This perturbation resulted in a significantly altered trajectory, with quaternary structural changes corresponding in many aspects to the experimental differences between complexed and uncomplexed state. The observed trend toward a smaller elbow angle and a higher flexion of the H-chain could also be seen in the third simulation, which was started from the x-ray structure of the complex. The changes were revealed to be a clear consequence of the complexation with the ligand because in the fourth simulation (started from the experimental complex structure after removal of the hapten) the Fab remained close to its initial structure. Analyses of the quaternary structure and the binding site of Fab NC6.8 are presented for all four simulations, and possible interpretations are discussed. |
| doi_str_mv | 10.1016/S0006-3495(00)76320-X |
| format | Article |
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The first simulation was started from the x-ray structure of the uncomplexed Fab and produced trajectory averages that closely match the crystallographic results. It allowed assessment of the flexibility of the Fab, revealing an elbow motion of the variable domains with respect to the constant domains. The second simulation was started from the uncomplexed x-ray structure after insertion of the ligand into the binding site. This perturbation resulted in a significantly altered trajectory, with quaternary structural changes corresponding in many aspects to the experimental differences between complexed and uncomplexed state. The observed trend toward a smaller elbow angle and a higher flexion of the H-chain could also be seen in the third simulation, which was started from the x-ray structure of the complex. The changes were revealed to be a clear consequence of the complexation with the ligand because in the fourth simulation (started from the experimental complex structure after removal of the hapten) the Fab remained close to its initial structure. Analyses of the quaternary structure and the binding site of Fab NC6.8 are presented for all four simulations, and possible interpretations are discussed.</description><identifier>ISSN: 0006-3495</identifier><identifier>EISSN: 1542-0086</identifier><identifier>DOI: 10.1016/S0006-3495(00)76320-X</identifier><identifier>PMID: 10919996</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Antigens ; Binding Sites, Antibody ; Biochemistry ; Computer Simulation ; Crystallography, X-Ray ; Haptens ; Immunoglobulin Fab Fragments - chemistry ; Immunoglobulin Heavy Chains - chemistry ; Ligands ; Models, Molecular ; Molecular biology ; Protein Conformation ; Proteins ; Stress, Mechanical ; Thermodynamics</subject><ispartof>Biophysical journal, 2000-08, Vol.79 (2), p.614-628</ispartof><rights>2000 The Biophysical Society</rights><rights>Copyright Biophysical Society Aug 2000</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c608t-55ce28733f487113bdc689d0c1b9ae794fb6a070e221083eaad8b9d4fbf3f4573</citedby><cites>FETCH-LOGICAL-c608t-55ce28733f487113bdc689d0c1b9ae794fb6a070e221083eaad8b9d4fbf3f4573</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/PMC1300962/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/S0006-3495(00)76320-X$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3548,27922,27923,45993,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/10919996$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sotriffer, Christoph A.</creatorcontrib><creatorcontrib>Rode, Bernd M.</creatorcontrib><creatorcontrib>Varga, Janos M.</creatorcontrib><creatorcontrib>Liedl, Klaus R.</creatorcontrib><title>Elbow Flexibility and Ligand-Induced Domain Rearrangements in Antibody Fab NC6.8: Large Effects of a Small Hapten</title><title>Biophysical journal</title><addtitle>Biophys J</addtitle><description>Four 700-ps molecular dynamics simulations were carried out to analyze the structural dynamics of the antigen-binding antibody fragment NC6.8, which is known to exhibit large structural changes upon complexation. The first simulation was started from the x-ray structure of the uncomplexed Fab and produced trajectory averages that closely match the crystallographic results. It allowed assessment of the flexibility of the Fab, revealing an elbow motion of the variable domains with respect to the constant domains. The second simulation was started from the uncomplexed x-ray structure after insertion of the ligand into the binding site. This perturbation resulted in a significantly altered trajectory, with quaternary structural changes corresponding in many aspects to the experimental differences between complexed and uncomplexed state. The observed trend toward a smaller elbow angle and a higher flexion of the H-chain could also be seen in the third simulation, which was started from the x-ray structure of the complex. The changes were revealed to be a clear consequence of the complexation with the ligand because in the fourth simulation (started from the experimental complex structure after removal of the hapten) the Fab remained close to its initial structure. Analyses of the quaternary structure and the binding site of Fab NC6.8 are presented for all four simulations, and possible interpretations are discussed.</description><subject>Amino Acid Sequence</subject><subject>Antigens</subject><subject>Binding Sites, Antibody</subject><subject>Biochemistry</subject><subject>Computer Simulation</subject><subject>Crystallography, X-Ray</subject><subject>Haptens</subject><subject>Immunoglobulin Fab Fragments - chemistry</subject><subject>Immunoglobulin Heavy Chains - chemistry</subject><subject>Ligands</subject><subject>Models, Molecular</subject><subject>Molecular biology</subject><subject>Protein Conformation</subject><subject>Proteins</subject><subject>Stress, Mechanical</subject><subject>Thermodynamics</subject><issn>0006-3495</issn><issn>1542-0086</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2000</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkcFuEzEQQC0EoqHwCSCLA4LDlrE36133AKpCQitFIFGQerO89mxwtWun9qaQv8dJqqpw4TTS-M14Zh4hLxmcMGDi_SUAiKKcyuotwLtalByKq0dkwqopLwAa8ZhM7pEj8iylawDGK2BPyREDyaSUYkJu5n0bftFFj79d63o3bqn2li7dKofiwtuNQUs_hUE7T7-hjlH7FQ7ox0Rz5syPrg12Sxe6pV9m4qQ5pUsdV0jnXYcmQ6Gjml4Ouu_puV6P6J-TJ53uE764i8fkx2L-fXZeLL9-vpidLQsjoBmLqjLIm7osu2lTM1a21ohGWjCslRprOe1aoaEG5JxBU6LWtmmlzekul1R1eUw-HPquN-2A1uSRo-7VOrpBx60K2qm_X7z7qVbhVrESQAqeG7y5axDDzQbTqAaXDPa99hg2SdW7a9a8yuDrf8DrsIk-L6c4q2rW8P041QEyMaQUsbufhIHaGVV7o2qnSwGovVF1letePVzjQdVBYQY-HgDMx7x1GFUyDn3W5mI2oGxw__niDxhssGg</recordid><startdate>20000801</startdate><enddate>20000801</enddate><creator>Sotriffer, Christoph A.</creator><creator>Rode, Bernd M.</creator><creator>Varga, Janos M.</creator><creator>Liedl, Klaus R.</creator><general>Elsevier Inc</general><general>Biophysical Society</general><scope>6I.</scope><scope>AAFTH</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>3V.</scope><scope>7QO</scope><scope>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8AF</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M2P</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20000801</creationdate><title>Elbow Flexibility and Ligand-Induced Domain Rearrangements in Antibody Fab NC6.8: Large Effects of a Small Hapten</title><author>Sotriffer, Christoph A. ; Rode, Bernd M. ; Varga, Janos M. ; Liedl, Klaus R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c608t-55ce28733f487113bdc689d0c1b9ae794fb6a070e221083eaad8b9d4fbf3f4573</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2000</creationdate><topic>Amino Acid Sequence</topic><topic>Antigens</topic><topic>Binding Sites, Antibody</topic><topic>Biochemistry</topic><topic>Computer Simulation</topic><topic>Crystallography, X-Ray</topic><topic>Haptens</topic><topic>Immunoglobulin Fab Fragments - chemistry</topic><topic>Immunoglobulin Heavy Chains - chemistry</topic><topic>Ligands</topic><topic>Models, Molecular</topic><topic>Molecular biology</topic><topic>Protein Conformation</topic><topic>Proteins</topic><topic>Stress, Mechanical</topic><topic>Thermodynamics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sotriffer, Christoph A.</creatorcontrib><creatorcontrib>Rode, Bernd M.</creatorcontrib><creatorcontrib>Varga, Janos M.</creatorcontrib><creatorcontrib>Liedl, Klaus R.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Biotechnology Research Abstracts</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>STEM Database</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>SIRS Editorial</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Biophysical journal</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sotriffer, Christoph A.</au><au>Rode, Bernd M.</au><au>Varga, Janos M.</au><au>Liedl, Klaus R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Elbow Flexibility and Ligand-Induced Domain Rearrangements in Antibody Fab NC6.8: Large Effects of a Small Hapten</atitle><jtitle>Biophysical journal</jtitle><addtitle>Biophys J</addtitle><date>2000-08-01</date><risdate>2000</risdate><volume>79</volume><issue>2</issue><spage>614</spage><epage>628</epage><pages>614-628</pages><issn>0006-3495</issn><eissn>1542-0086</eissn><abstract>Four 700-ps molecular dynamics simulations were carried out to analyze the structural dynamics of the antigen-binding antibody fragment NC6.8, which is known to exhibit large structural changes upon complexation. The first simulation was started from the x-ray structure of the uncomplexed Fab and produced trajectory averages that closely match the crystallographic results. It allowed assessment of the flexibility of the Fab, revealing an elbow motion of the variable domains with respect to the constant domains. The second simulation was started from the uncomplexed x-ray structure after insertion of the ligand into the binding site. This perturbation resulted in a significantly altered trajectory, with quaternary structural changes corresponding in many aspects to the experimental differences between complexed and uncomplexed state. The observed trend toward a smaller elbow angle and a higher flexion of the H-chain could also be seen in the third simulation, which was started from the x-ray structure of the complex. The changes were revealed to be a clear consequence of the complexation with the ligand because in the fourth simulation (started from the experimental complex structure after removal of the hapten) the Fab remained close to its initial structure. Analyses of the quaternary structure and the binding site of Fab NC6.8 are presented for all four simulations, and possible interpretations are discussed.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>10919996</pmid><doi>10.1016/S0006-3495(00)76320-X</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; ScienceDirect Journals (5 years ago - present); PubMed Central |
| subjects | Amino Acid Sequence Antigens Binding Sites, Antibody Biochemistry Computer Simulation Crystallography, X-Ray Haptens Immunoglobulin Fab Fragments - chemistry Immunoglobulin Heavy Chains - chemistry Ligands Models, Molecular Molecular biology Protein Conformation Proteins Stress, Mechanical Thermodynamics |
| title | Elbow Flexibility and Ligand-Induced Domain Rearrangements in Antibody Fab NC6.8: Large Effects of a Small Hapten |
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