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PDBsum entry 1ovh
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Testing a flexible-Receptor docking algorithm in a model binding site.
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Authors
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B.Q.Wei,
L.H.Weaver,
A.M.Ferrari,
B.W.Matthews,
B.K.Shoichet.
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Ref.
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J Mol Biol, 2004,
337,
1161-1182.
[DOI no: ]
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PubMed id
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Abstract
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Sampling receptor flexibility is challenging for database docking. We consider a
method that treats multiple flexible regions of the binding site independently,
recombining them to generate different discrete conformations. This algorithm
scales linearly rather than exponentially with the receptor's degrees of
freedom. The method was first evaluated for its ability to identify known
ligands of a hydrophobic cavity mutant of T4 lysozyme (L99A). Some 200000
molecules of the Available Chemical Directory (ACD) were docked against an
ensemble of cavity conformations. Surprisingly, the enrichment of known ligands
from among a much larger number of decoys in the ACD was worse than simply
docking to the apo conformation alone. Large decoys, accommodated in the larger
cavity conformations sampled in the ensemble, were ranked better than known
small ligands. The calculation was redone with an energy correction term that
considered the cost of forming the larger cavity conformations. Enrichment
improved, as did the balance between high-ranking large and small ligands. In a
second retrospective test, the ACD was docked against a conformational ensemble
of thymidylate synthase. Compared to docking against individual enzyme
conformations, the flexible receptor docking approach improved enrichment of
known ligands. Including a receptor conformational energy weighting term
improved enrichment further. To test the method prospectively, the ACD database
was docked against another cavity mutant of lysozyme (L99A/M102Q). A total of 18
new compounds predicted to bind this polar cavity and to change its conformation
were tested experimentally; 14 were found to bind. The bound structures for
seven ligands were determined by X-ray crystallography. The predicted geometries
of these ligands all corresponded to the observed geometries to within 0.7A RMSD
or better. Significant conformational changes of the cavity were observed in all
seven complexes. In five structures, part of the observed accommodations were
correctly predicted; in two structures, the receptor conformational changes were
unanticipated and thus never sampled. These results suggest that although
sampling receptor flexibility can lead to novel ligands that would have been
missed when docking a rigid structure, it is also important to consider receptor
conformational energy.
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Figure 6.
Figure 6. Stereo views of difference electron density maps
for seven ligands bound to L99A/M102Q. a, 2-n-Propyl aniline; b,
2-allyl-6-methyl phenol; c, 3-fluoro-2-methyl aniline; d,
2-allyl phenol; e, 2-chloro-6-methyl aniline; f,
4-fluorophenethyl alcohol; and g, N-allyl aniline. The
coefficients are (F[o] -F[c]), where the F[o] are the observed
structure amplitudes for the ligand-bound complex and the F[c]
and phases were calculated from the refined model with all atoms
removed from the cavity. Maps are contoured at +3s (continuous
lines) and -3s (broken lines).
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Figure 8.
Figure 8. Docking against the apo L99A/M102Q cavity (PDB
entry 1LGU) led to incorrect prediction of the binding geometry
of a, 2-chloro-6-methyl aniline and b, 3-fluoro-2-methyl
aniline. Color scheme is the same as in Figure 7. The pictures
are in stereo.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2004,
337,
1161-1182)
copyright 2004.
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Secondary reference #1
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Title
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A model binding site for testing scoring functions in molecular docking.
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Authors
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B.Q.Wei,
W.A.Baase,
L.H.Weaver,
B.W.Matthews,
B.K.Shoichet.
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Ref.
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J Mol Biol, 2002,
322,
339-355.
[DOI no: ]
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PubMed id
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Figure 9.
Figure 9. Difference density map
for 3-chlorophenol bound to
L99A/M102Q. The coefficients are
(Fo 2 Fc) where the Fo are the
structure amplitudes observed for
the 3-chlorophenol-bound complex
and the Fc and phases were calcu-
lated from the refined model with
all ligand atoms removed from the
binding site. The map is at 1.85 A
š
resolution and contoured at
+3s
(continuous lines) and 23s (broken
lines).
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Figure 10.
Figure 10. Difference density
map for 3-methylpyrrole bound
to L99A/M102Q. The coefficients
were defined as in Figure 9. The
map is at 2.0 A
š
resolution and con-
toured at
+3s
(continuous lines)
and 23s (broken lines).
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The above figures are
reproduced from the cited reference
with permission from Elsevier
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