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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Reengineering Rate-Limiting, Millisecond Enzyme Motions by Introduction of an Unnatural Amino Acid</title>
<author><name sortKey="Watt, Eric D" sort="Watt, Eric D" uniqKey="Watt E" first="Eric D." last="Watt">Eric D. Watt</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rivalta, Ivan" sort="Rivalta, Ivan" uniqKey="Rivalta I" first="Ivan" last="Rivalta">Ivan Rivalta</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Whittier, Sean K" sort="Whittier, Sean K" uniqKey="Whittier S" first="Sean K." last="Whittier">Sean K. Whittier</name>
<affiliation><nlm:aff id="aff2">Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batista, Victor S" sort="Batista, Victor S" uniqKey="Batista V" first="Victor S." last="Batista">Victor S. Batista</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Loria, J Patrick" sort="Loria, J Patrick" uniqKey="Loria J" first="J. Patrick" last="Loria">J. Patrick Loria</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">21767494</idno>
<idno type="pmc">3136797</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136797</idno>
<idno type="RBID">PMC:3136797</idno>
<idno type="doi">10.1016/j.bpj.2011.05.039</idno>
<date when="2011">2011</date>
<idno type="wicri:Area/Pmc/Corpus">000057</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000057</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Reengineering Rate-Limiting, Millisecond Enzyme Motions by Introduction of an Unnatural Amino Acid</title>
<author><name sortKey="Watt, Eric D" sort="Watt, Eric D" uniqKey="Watt E" first="Eric D." last="Watt">Eric D. Watt</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Rivalta, Ivan" sort="Rivalta, Ivan" uniqKey="Rivalta I" first="Ivan" last="Rivalta">Ivan Rivalta</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Whittier, Sean K" sort="Whittier, Sean K" uniqKey="Whittier S" first="Sean K." last="Whittier">Sean K. Whittier</name>
<affiliation><nlm:aff id="aff2">Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Batista, Victor S" sort="Batista, Victor S" uniqKey="Batista V" first="Victor S." last="Batista">Victor S. Batista</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
<author><name sortKey="Loria, J Patrick" sort="Loria, J Patrick" uniqKey="Loria J" first="J. Patrick" last="Loria">J. Patrick Loria</name>
<affiliation><nlm:aff id="aff1">Department of Chemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
<affiliation><nlm:aff id="aff2">Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut</nlm:aff>
</affiliation>
</author>
</analytic>
<series><title level="j">Biophysical Journal</title>
<idno type="ISSN">0006-3495</idno>
<idno type="eISSN">1542-0086</idno>
<imprint><date when="2011">2011</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Rate-limiting millisecond motions in wild-type (WT) Ribonuclease A (RNase A) are modulated by histidine 48. Here, we incorporate an unnatural amino acid, thia-methylimidazole, at this site (H48C-4MI) to investigate the effects of a single residue on protein motions over multiple timescales and on enzyme catalytic turnover. Molecular dynamics simulations reveal that H48C-4MI retains some crucial WT-like hydrogen bonding interactions but the extent of protein-wide correlated motions in the nanosecond regime is decreased relative to WT. NMR Carr-Purcell-Meiboom-Gill relaxation dispersion experiments demonstrate that millisecond conformational motions in H48C-4MI are present over a similar pH range compared to WT. Furthermore, incorporation of this nonnatural amino acid allows retention of WT-like catalytic activity over the full pH range. These studies demonstrate that the complexity of the protein energy landscape during the catalytic cycle can be maintained using unnatural amino acids, which may prove useful in enzyme design efforts.</p>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Biophys J</journal-id>
<journal-title-group><journal-title>Biophysical Journal</journal-title>
</journal-title-group>
<issn pub-type="ppub">0006-3495</issn>
<issn pub-type="epub">1542-0086</issn>
<publisher><publisher-name>The Biophysical Society</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">21767494</article-id>
<article-id pub-id-type="pmc">3136797</article-id>
<article-id pub-id-type="publisher-id">BPJ2923</article-id>
<article-id pub-id-type="doi">10.1016/j.bpj.2011.05.039</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Protein</subject>
</subj-group>
</article-categories>
<title-group><article-title>Reengineering Rate-Limiting, Millisecond Enzyme Motions by Introduction of an Unnatural Amino Acid</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Watt</surname>
<given-names>Eric D.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rivalta</surname>
<given-names>Ivan</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Whittier</surname>
<given-names>Sean K.</given-names>
</name>
<xref rid="aff2" ref-type="aff">‡</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Batista</surname>
<given-names>Victor S.</given-names>
</name>
<xref rid="aff1" ref-type="aff">†</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Loria</surname>
<given-names>J. Patrick</given-names>
</name>
<email>patrick.loria@yale.edu</email>
<xref rid="aff1" ref-type="aff">†</xref>
<xref rid="aff2" ref-type="aff">‡</xref>
<xref rid="cor1" ref-type="corresp">∗</xref>
</contrib>
</contrib-group>
<aff id="aff1"><label>†</label>
Department of Chemistry, Yale University, New Haven, Connecticut</aff>
<aff id="aff2"><label>‡</label>
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut</aff>
<author-notes><corresp id="cor1"><label>∗</label>
Corresponding author <email>patrick.loria@yale.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="pmc-release"><day>20</day>
<month>7</month>
<year>2011</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
. </pmc-comment>
<pub-date pub-type="ppub"><day>20</day>
<month>7</month>
<year>2011</year>
</pub-date>
<volume>101</volume>
<issue>2</issue>
<fpage>411</fpage>
<lpage>420</lpage>
<history><date date-type="received"><day>28</day>
<month>3</month>
<year>2011</year>
</date>
<date date-type="accepted"><day>19</day>
<month>5</month>
<year>2011</year>
</date>
</history>
<permissions><copyright-statement>© 2011 by the Biophysical Society.</copyright-statement>
<copyright-year>2011</copyright-year>
<copyright-holder>Biophysical Society</copyright-holder>
</permissions>
<abstract><p>Rate-limiting millisecond motions in wild-type (WT) Ribonuclease A (RNase A) are modulated by histidine 48. Here, we incorporate an unnatural amino acid, thia-methylimidazole, at this site (H48C-4MI) to investigate the effects of a single residue on protein motions over multiple timescales and on enzyme catalytic turnover. Molecular dynamics simulations reveal that H48C-4MI retains some crucial WT-like hydrogen bonding interactions but the extent of protein-wide correlated motions in the nanosecond regime is decreased relative to WT. NMR Carr-Purcell-Meiboom-Gill relaxation dispersion experiments demonstrate that millisecond conformational motions in H48C-4MI are present over a similar pH range compared to WT. Furthermore, incorporation of this nonnatural amino acid allows retention of WT-like catalytic activity over the full pH range. These studies demonstrate that the complexity of the protein energy landscape during the catalytic cycle can be maintained using unnatural amino acids, which may prove useful in enzyme design efforts.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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