Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations
Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-p...
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| creator | Esposito, Gennaro Berni, Rodolfo Corazza, Alessandra Dongmo Foumthuim, Cedrix J. Fogolari, Federico |
| description | Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects. |
| doi_str_mv | 10.1155/2018/7480749 |
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Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.</description><identifier>ISSN: 2314-6133</identifier><identifier>EISSN: 2314-6141</identifier><identifier>DOI: 10.1155/2018/7480749</identifier><identifier>PMID: 29967786</identifier><language>eng</language><publisher>Cairo, Egypt: Hindawi Publishing Corporation</publisher><subject>Amino acids ; Analysis ; Dimers ; Dynamic stability ; Free energy ; Macromolecular Substances ; Models, Molecular ; Molecular chains ; Molecular dynamics ; Molecular Dynamics Simulation ; Molecular physics ; Monomers ; Mutants ; Mutation ; Physics ; Prealbumin - chemistry ; Prealbumin - genetics ; Protein structure ; Proteins ; Simulation ; Structural stability ; Thermodynamics ; Trajectory analysis ; Transthyretin</subject><ispartof>BioMed research international, 2018-01, Vol.2018 (2018), p.1-14</ispartof><rights>Copyright © 2018 Cedrix J. Dongmo Foumthuim et al.</rights><rights>COPYRIGHT 2018 John Wiley & Sons, Inc.</rights><rights>Copyright © 2018 Cedrix J. Dongmo Foumthuim et al.; This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</rights><rights>Copyright © 2018 Cedrix J. Dongmo Foumthuim et al. 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c499t-969ecfa7d6c7fa34f88f5e619b2e3f0e222d49a678bcf9447bb9996ce1c5ffa53</citedby><cites>FETCH-LOGICAL-c499t-969ecfa7d6c7fa34f88f5e619b2e3f0e222d49a678bcf9447bb9996ce1c5ffa53</cites><orcidid>0000-0001-9862-250X ; 0000-0002-8095-0289</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008865/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008865/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53770,53772</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29967786$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Domene, Carmen</contributor><contributor>Carmen Domene</contributor><creatorcontrib>Esposito, Gennaro</creatorcontrib><creatorcontrib>Berni, Rodolfo</creatorcontrib><creatorcontrib>Corazza, Alessandra</creatorcontrib><creatorcontrib>Dongmo Foumthuim, Cedrix J.</creatorcontrib><creatorcontrib>Fogolari, Federico</creatorcontrib><title>Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations</title><title>BioMed research international</title><addtitle>Biomed Res Int</addtitle><description>Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.</description><subject>Amino acids</subject><subject>Analysis</subject><subject>Dimers</subject><subject>Dynamic stability</subject><subject>Free energy</subject><subject>Macromolecular Substances</subject><subject>Models, Molecular</subject><subject>Molecular chains</subject><subject>Molecular dynamics</subject><subject>Molecular Dynamics Simulation</subject><subject>Molecular physics</subject><subject>Monomers</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Physics</subject><subject>Prealbumin - chemistry</subject><subject>Prealbumin - genetics</subject><subject>Protein structure</subject><subject>Proteins</subject><subject>Simulation</subject><subject>Structural stability</subject><subject>Thermodynamics</subject><subject>Trajectory analysis</subject><subject>Transthyretin</subject><issn>2314-6133</issn><issn>2314-6141</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>RHX</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNqNkUuLFDEURoMozjDOzrUUuBG0nbwqj43QjE8YcWG7E0IqdTOdoSoZkyql_70pu6d9rMwm4eZwbm4-hB4T_JKQtr2gmKgLyRWWXN9Dp5QRvhKEk_vHM2Mn6LyUG1yXIgJr8RCdUK2FlEqcoq-vd9GOwZXGxr7ZbCGPqb8rJd9sso1l2u4yTCE261KSC3YKKTY-p7H5mAZw82Bzc_R8DmMtLEh5hB54OxQ4P-xn6MvbN5vL96urT-8-XK6vVo5rPa200OC8lb1w0lvGvVK-BUF0R4F5DJTSnmsrpOqc15zLrtN1AAfEtd7blp2hV3vv7dyN0DuIU7aDuc1htHlnkg3m75sYtuY6fTei_okSi-DZQZDTtxnKZMZQHAyDjZDmYigWTBJGBa_o03_QmzTnWMerVCtrIPqX8EBd2wFMiD7Vvm6RmrWgRGHMOKvUiz3lciolgz8-mWCz5GuWfM0h34o_-XPMI3yXZgWe74FtiL39Ef5TB5UBb3_ThKqWE_YThDq3_A</recordid><startdate>20180101</startdate><enddate>20180101</enddate><creator>Esposito, Gennaro</creator><creator>Berni, Rodolfo</creator><creator>Corazza, Alessandra</creator><creator>Dongmo Foumthuim, Cedrix J.</creator><creator>Fogolari, Federico</creator><general>Hindawi Publishing Corporation</general><general>Hindawi</general><general>John Wiley & Sons, Inc</general><general>Hindawi Limited</general><scope>ADJCN</scope><scope>AHFXO</scope><scope>RHU</scope><scope>RHW</scope><scope>RHX</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>7QL</scope><scope>7QO</scope><scope>7T7</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>CWDGH</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9862-250X</orcidid><orcidid>https://orcid.org/0000-0002-8095-0289</orcidid></search><sort><creationdate>20180101</creationdate><title>Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations</title><author>Esposito, Gennaro ; Berni, Rodolfo ; Corazza, Alessandra ; Dongmo Foumthuim, Cedrix J. ; Fogolari, Federico</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c499t-969ecfa7d6c7fa34f88f5e619b2e3f0e222d49a678bcf9447bb9996ce1c5ffa53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Amino acids</topic><topic>Analysis</topic><topic>Dimers</topic><topic>Dynamic stability</topic><topic>Free energy</topic><topic>Macromolecular Substances</topic><topic>Models, Molecular</topic><topic>Molecular chains</topic><topic>Molecular dynamics</topic><topic>Molecular Dynamics Simulation</topic><topic>Molecular physics</topic><topic>Monomers</topic><topic>Mutants</topic><topic>Mutation</topic><topic>Physics</topic><topic>Prealbumin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>BioMed research international</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Esposito, Gennaro</au><au>Berni, Rodolfo</au><au>Corazza, Alessandra</au><au>Dongmo Foumthuim, Cedrix J.</au><au>Fogolari, Federico</au><au>Domene, Carmen</au><au>Carmen Domene</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations</atitle><jtitle>BioMed research international</jtitle><addtitle>Biomed Res Int</addtitle><date>2018-01-01</date><risdate>2018</risdate><volume>2018</volume><issue>2018</issue><spage>1</spage><epage>14</epage><pages>1-14</pages><issn>2314-6133</issn><eissn>2314-6141</eissn><abstract>Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. 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| subjects | Amino acids Analysis Dimers Dynamic stability Free energy Macromolecular Substances Models, Molecular Molecular chains Molecular dynamics Molecular Dynamics Simulation Molecular physics Monomers Mutants Mutation Physics Prealbumin - chemistry Prealbumin - genetics Protein structure Proteins Simulation Structural stability Thermodynamics Trajectory analysis Transthyretin |
| title | Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations |
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