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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Polarizable Atomic Multipole X-Ray Refinement: Hydration Geometry and Application to Macromolecules</title><author><name sortKey="Fenn, Timothy D" sort="Fenn, Timothy D" uniqKey="Fenn T" first="Timothy D." last="Fenn">Timothy D. Fenn</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Schnieders, Michael J" sort="Schnieders, Michael J" uniqKey="Schnieders M" first="Michael J." last="Schnieders">Michael J. Schnieders</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Brunger, Axel T" sort="Brunger, Axel T" uniqKey="Brunger A" first="Axel T." last="Brunger">Axel T. Brunger</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Pande, Vijay S" sort="Pande, Vijay S" uniqKey="Pande V" first="Vijay S." last="Pande">Vijay S. Pande</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">20550911</idno><idno type="pmc">2884231</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884231</idno><idno type="RBID">PMC:2884231</idno><idno type="doi">10.1016/j.bpj.2010.02.057</idno><date when="2010">2010</date><idno type="wicri:Area/Pmc/Corpus">000358</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Polarizable Atomic Multipole X-Ray Refinement: Hydration Geometry and Application to Macromolecules</title><author><name sortKey="Fenn, Timothy D" sort="Fenn, Timothy D" uniqKey="Fenn T" first="Timothy D." last="Fenn">Timothy D. Fenn</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation></author><author><name sortKey="Schnieders, Michael J" sort="Schnieders, Michael J" uniqKey="Schnieders M" first="Michael J." last="Schnieders">Michael J. Schnieders</name><affiliation><nlm:aff id="aff3"></nlm:aff></affiliation></author><author><name sortKey="Brunger, Axel T" sort="Brunger, Axel T" uniqKey="Brunger A" first="Axel T." last="Brunger">Axel T. Brunger</name><affiliation><nlm:aff id="aff1"></nlm:aff></affiliation><affiliation><nlm:aff id="aff2"></nlm:aff></affiliation><affiliation><nlm:aff id="aff4"></nlm:aff></affiliation><affiliation><nlm:aff id="aff5"></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"></nlm:aff></affiliation></author><author><name sortKey="Pande, Vijay S" sort="Pande, Vijay S" uniqKey="Pande V" first="Vijay S." last="Pande">Vijay S. Pande</name><affiliation><nlm:aff id="aff3"></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="2010">2010</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Abstract</title><p>We recently developed a polarizable atomic multipole refinement method assisted by the AMOEBA force field for macromolecular crystallography. Compared to standard refinement procedures, the method uses a more rigorous treatment of x-ray scattering and electrostatics that can significantly improve the resultant information contained in an atomic model. We applied this method to high-resolution lysozyme and trypsin data sets, and validated its utility for precisely describing biomolecular electron density, as indicated by a 0.4–0.6% decrease in the <italic>R</italic>- and <italic>R</italic><sub>free</sub>-values, and a corresponding decrease in the relative energy of 0.4–0.8 Kcal/mol/residue. The re-refinements illustrate the ability of force-field electrostatics to orient water networks and catalytically relevant hydrogens, which can be used to make predictions regarding active site function, activity, and protein-ligand interaction energies. Re-refinement of a DNA crystal structure generates the zigzag spine pattern of hydrogen bonding in the minor groove without manual intervention. The polarizable atomic multipole electrostatics model implemented in the AMOEBA force field is applicable and informative for crystal structures solved at any resolution.</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>Biophysical Journal</journal-title><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">20550911</article-id><article-id pub-id-type="pmc">2884231</article-id><article-id pub-id-type="publisher-id">BPJ1731</article-id><article-id pub-id-type="doi">10.1016/j.bpj.2010.02.057</article-id><article-categories><subj-group subj-group-type="heading"><subject>Protein</subject></subj-group></article-categories><title-group><article-title>Polarizable Atomic Multipole X-Ray Refinement: Hydration Geometry and Application to Macromolecules</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Fenn</surname><given-names>Timothy D.</given-names></name><xref rid="aff1" ref-type="aff">†</xref><xref rid="aff2" ref-type="aff">‡</xref><xref rid="fn1" ref-type="fn">▵</xref></contrib><contrib contrib-type="author"><name><surname>Schnieders</surname><given-names>Michael J.</given-names></name><xref rid="aff3" ref-type="aff">§</xref><xref rid="fn1" ref-type="fn">▵</xref></contrib><contrib contrib-type="author"><name><surname>Brunger</surname><given-names>Axel T.</given-names></name><xref rid="aff1" ref-type="aff">†</xref><xref rid="aff2" ref-type="aff">‡</xref><xref rid="aff4" ref-type="aff">¶</xref><xref rid="aff5" ref-type="aff">‖</xref><xref rid="aff6" ref-type="aff">††</xref></contrib><contrib contrib-type="author"><name><surname>Pande</surname><given-names>Vijay S.</given-names></name><email>pande@stanford.edu</email><xref rid="aff3" ref-type="aff">§</xref><xref rid="cor1" ref-type="corresp">∗</xref></contrib></contrib-group><aff id="aff1"><addr-line><sup>†</sup>Department of Molecular and Cellular Physiology, Stanford University, Stanford, California</addr-line></aff><aff id="aff2"><addr-line><sup>‡</sup>Howard Hughes Medical Institute, Stanford University, Stanford, California</addr-line></aff><aff id="aff3"><addr-line><sup>§</sup>Department of Chemistry, Stanford University, Stanford, California</addr-line></aff><aff id="aff4"><addr-line><sup>¶</sup>Department of Neurology and Neurological Sciences, Stanford University, Stanford, California</addr-line></aff><aff id="aff5"><addr-line><sup>‖</sup>Department of Structural Biology, Stanford University, Stanford, California</addr-line></aff><aff id="aff6"><addr-line><sup>††</sup>Department of Photon Sciences, Stanford University, Stanford, California</addr-line></aff><author-notes><corresp id="cor1"><label>∗</label>Corresponding author <email>pande@stanford.edu</email></corresp><fn id="fn1"><label>▵</label><p>Timothy D. Fenn and Michael J. Schnieders contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>16</day><month>6</month><year>2010</year></pub-date><volume>98</volume><issue>12</issue><fpage>2984</fpage><lpage>2992</lpage><history><date date-type="received"><day>30</day><month>11</month><year>2009</year></date><date date-type="accepted"><day>17</day><month>2</month><year>2010</year></date></history><permissions><copyright-statement>© 2010 by the Biophysical Society..</copyright-statement><copyright-year>2010</copyright-year><copyright-holder>Biophysical Society</copyright-holder><license><p>This document may be redistributed and reused, subject to <ext-link ext-link-type="uri" xlink:href="http://www.elsevier.com/wps/find/authorsview.authors/supplementalterms1.0">certain conditions</ext-link>.</p></license></permissions><abstract><title>Abstract</title><p>We recently developed a polarizable atomic multipole refinement method assisted by the AMOEBA force field for macromolecular crystallography. Compared to standard refinement procedures, the method uses a more rigorous treatment of x-ray scattering and electrostatics that can significantly improve the resultant information contained in an atomic model. We applied this method to high-resolution lysozyme and trypsin data sets, and validated its utility for precisely describing biomolecular electron density, as indicated by a 0.4–0.6% decrease in the <italic>R</italic>- and <italic>R</italic><sub>free</sub>-values, and a corresponding decrease in the relative energy of 0.4–0.8 Kcal/mol/residue. The re-refinements illustrate the ability of force-field electrostatics to orient water networks and catalytically relevant hydrogens, which can be used to make predictions regarding active site function, activity, and protein-ligand interaction energies. Re-refinement of a DNA crystal structure generates the zigzag spine pattern of hydrogen bonding in the minor groove without manual intervention. The polarizable atomic multipole electrostatics model implemented in the AMOEBA force field is applicable and informative for crystal structures solved at any resolution.</p></abstract></article-meta></front><floats-wrap><fig id="fig1"><label>Figure 1</label><caption><p>Final model of the lysozyme (PDB ID: 2VB1) active site for the deposited structure (<italic>A</italic>) and after the addition of hydrogens and re-refinement with AMOEBA forces and the x-ray data (<italic>B</italic>). Shown are the nucleophile (Asp-52), general acid (Glu-35), and surrounding water molecules. Water molecules without hydrogens are depicted as red crosses. Hydrogen bonds are drawn as dashed lines, and electron density represents 2<italic>F</italic><sub>o</sub>-<italic>F</italic><sub>c</sub><italic>σ</italic><sub>A</sub>-weighted maps contoured at 3.0 <italic>σ</italic>. Glu-35 was modeled as protonated based on bond lengths, available data, and crystallization conditions. All figures were generated using POVScript+ (<xref rid="bib64" ref-type="bibr">64</xref>) and rendered using POVRay.</p></caption><graphic xlink:href="gr1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Tyr-53 from the lysozyme model with electron density (<italic>σ</italic><sub>A</sub>-weighted <italic>F</italic><sub>o</sub>-<italic>F</italic><sub>c</sub> maps, contoured at 1.8 <italic>σ</italic>) obtained before (<italic>purple</italic>) and after (<italic>green</italic>) introduction of the aspherical and anisotropic scattering model. Also highlighted are the hydrogen positions before (<italic>red</italic>) and after (<italic>blue</italic>) the same procedure. Note the average lengthening of X-H bonds and the disappearance of difference density at bond centers.</p></caption><graphic xlink:href="gr2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Trypsin catalytic triad prior (<italic>purple</italic> hydroxyl group on Ser-195) and after (<italic>red</italic> hydroxyl group on Ser-195) introduction of the electrostatic model. The oxyanion hole is depicted with the thick black dashed line. Residue numbering corresponds to trypsin from <italic>Fusarium oxysporum</italic>. Green arrows represent polarization vectors at the displayed atomic positions. A 3.0 Å vector length corresponds to 1 D.</p></caption><graphic xlink:href="gr3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Zigzag spine of hydration in the DNA minor groove. Bases in gray are from the 3′→5′ strand, and bases in black are derived from the 5′→3′ strand. Shown is the AATT subsequence of the deposited structure (<italic>A</italic>) and after AMOEBA-assisted refinement with the x-ray data (<italic>B</italic>), with the primary and secondary layers of water forming the zigzag pattern. Green arrows represent polarization vectors originating from the water oxygens, and a 3.0 Å vector length corresponds to 1 D (average vector length: 1.5 Å).</p></caption><graphic xlink:href="gr4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Hydration shell around one of the magnesium ions (shown in <italic>gold</italic>) in the re-refined crystal structure of the DNA 9mer (GCGAATTCG). Extensive hydrogen bonding is present with both DNA strands and a phosphate from a crystallographically related molecule (shown in <italic>purple</italic> and <italic>maroon</italic> at the bottom of the figure). Discretely disordered waters are indicated with cyan hydrogen bonds for clarity. All distances shown are given in angstroms. The magnesium is rendered according to thermal displacement parameters at the 20% isoprobability level.</p></caption><graphic xlink:href="gr5"></graphic></fig><table-wrap position="float" id="tbl1"><label>Table 1</label><caption><p>Refinement statistics</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2">Molecule</th><th rowspan="2"><italic>d</italic><sub>min</sub> (Å)</th><th rowspan="2">Scattering model</th><th rowspan="2"><italic>N</italic><sub>par</sub></th><th rowspan="2"><italic>N</italic><sub>hkl</sub></th><th colspan="2"><italic>R</italic><sub>work</sub> / <italic>R</italic><sub>free</sub> (%)<hr></hr></th><th rowspan="2">Relative energy (Kcal/mol)</th></tr><tr><th><italic>F</italic><sub>obs</sub>/<italic>σ</italic>(<italic>F</italic><sub>obs</sub>)>0</th><th><italic>F</italic><sub>obs</sub>/<italic>σ</italic>(<italic>F</italic><sub>obs</sub>)>3</th></tr></thead><tbody><tr><td>Lysozyme</td><td align="char">0.65</td><td>IAM</td><td align="char">20681</td><td align="char">187165</td><td align="char">8.40 / 9.05</td><td align="char">8.21 / 8.87</td><td>109.3</td></tr><tr><td></td><td></td><td>AMOEBA-IAS</td><td align="char">21887</td><td align="char">187165</td><td align="char">7.87 / 8.60</td><td align="char">7.66 / 8.38</td><td>0</td></tr><tr><td>Trypsin</td><td align="char">0.84</td><td>IAM</td><td align="char">29523</td><td align="char">138150</td><td align="char">10.90 / 11.62</td><td align="char">10.60 / 11.28</td><td>93.4</td></tr><tr><td></td><td></td><td>AMOEBA-IAS</td><td align="char">30597</td><td align="char">138150</td><td align="char">10.45 / 11.11</td><td align="char">10.16 / 10.77</td><td>0</td></tr><tr><td>DNA<xref rid="tblfn1" ref-type="table-fn">∗</xref></td><td align="char">0.89</td><td>IAM</td><td align="char">7786</td><td align="char">30475</td><td align="char">14.21 / 16.59</td><td align="char">14.10 / 16.37</td><td>NA</td></tr></tbody></table><table-wrap-foot><fn id="tblfn1"><label>∗</label><p>For the DNA case, only the IAM model with AMOEBA chemical forces was used, because the AMOEBA-IAS model did not lead to a significant statistical improvement (data not shown).</p></fn></table-wrap-foot></table-wrap><table-wrap position="float" id="tbl2"><label>Table 2</label><caption><p>Protonation state assignment for HEWL</p></caption><table frame="hsides" rules="groups"><thead><tr><th>Residue</th><th>pK<sub>a</sub><xref rid="tblfn2" ref-type="table-fn">∗</xref></th><th>Neutron assigment<xref rid="tblfn3" ref-type="table-fn">†</xref></th><th>C-O bond lengths<xref rid="tblfn4" ref-type="table-fn">‡</xref></th><th>C-O bond lengths<xref rid="tblfn5" ref-type="table-fn">§</xref></th><th>Assignment</th></tr></thead><tbody><tr><td>Glu-7</td><td align="char">2.85 ± 0.25</td><td>neutral</td><td align="char">1.28, 1.25</td><td align="char">1.28, 1.24</td><td>charged</td></tr><tr><td>Asp-18</td><td align="char">2.66 ± 0.08</td><td>charged</td><td align="char">1.25, 1.24</td><td align="char">1.25, 1.25</td><td>charged</td></tr><tr><td>Glu-35</td><td align="char">6.20 ± 0.10</td><td>neutral</td><td align="char">1.33, 1.23</td><td align="char">1.32, 1.23</td><td>neutral</td></tr><tr><td>Asp-48</td><td>< 2.5</td><td>charged</td><td align="char">1.27, 1.22</td><td align="char">1.27, 1.22</td><td>charged</td></tr><tr><td>Asp-52</td><td align="char">3.68 ± 0.08</td><td>charged</td><td align="char">1.27, 1.22</td><td align="char">1.27, 1.22</td><td>charged</td></tr><tr><td>Asp-66</td><td>< 2.0</td><td>charged</td><td align="char">1.27, 1.26</td><td align="char">1.27, 1.25</td><td>charged</td></tr><tr><td>Asp-87</td><td align="char">2.07 ± 0.15</td><td>charged</td><td align="char">1.27, 1.24</td><td align="char">1.27, 1.24</td><td>charged</td></tr><tr><td>Asp-101</td><td align="char">4.09 ± 0.07</td><td>charged</td><td align="char">1.30, 1.20</td><td align="char">1.31, 1.20</td><td>neutral</td></tr><tr><td>Asp-119</td><td align="char">3.20 ± 0.09</td><td>charged</td><td align="char">1.27, 1.24</td><td align="char">1.26, 1.24</td><td>charged</td></tr><tr><td>Leu-129</td><td align="char">2.75 ± 0.12</td><td>charged</td><td align="char">1.26, 1.24</td><td align="char">1.26, 1.24</td><td>charged</td></tr><tr><td>His-15</td><td align="char">5.36 ± 0.07</td><td>charged</td><td>-</td><td>-</td><td>charged</td></tr></tbody></table><table-wrap-foot><fn id="tblfn2"><label>∗</label><p>pK<sub>a</sub> standard deviation from Bartik et al. (<xref rid="bib36" ref-type="bibr">36</xref>) measured by monitoring proton chemical shifts by NMR during titration at 35°C and 100 mM salt.</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn3"><label>†</label><p>Assignments from a 1.7 Å neutron diffraction study at pH 4.7 by Bon et al. (<xref rid="bib37" ref-type="bibr">37</xref>).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn4"><label>‡</label><p>Bond lengths from the re-refined lysozyme structure reported here. For protonated carboxylic acids, the equilibrium C=O and C-OH bond lengths are 1.21 and 1.31 Å, respectively. This assumes that that the proton is not shared between the oxygen atoms. For a charged carboxylic acid, the equilibrium C-O bond lengths are both 1.26 Å (<xref rid="bib35" ref-type="bibr">35</xref>).</p></fn></table-wrap-foot><table-wrap-foot><fn id="tblfn5"><label>§</label><p>Bond lengths from re-refinement of the lysozyme structure with the force field turned off (i.e., refined against the x-ray diffraction data only).</p></fn></table-wrap-foot></table-wrap></floats-wrap></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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