2ou0
From Proteopedia
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'''1-methylpyrrole in complex with T4 Lysozyme L99A''' | '''1-methylpyrrole in complex with T4 Lysozyme L99A''' | ||
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[[Category: Graves, A P.]] | [[Category: Graves, A P.]] | ||
[[Category: Shoichet, B K.]] | [[Category: Shoichet, B K.]] | ||
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| - | [[Category: | + | [[Category: Protein-ligand complex]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 11:39:01 2008'' | |
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Revision as of 08:39, 4 May 2008
1-methylpyrrole in complex with T4 Lysozyme L99A
Overview
A central challenge in structure-based ligand design is the accurate prediction of binding free energies. Here we apply alchemical free energy calculations in explicit solvent to predict ligand binding in a model cavity in T4 lysozyme. Even in this simple site, there are challenges. We made systematic improvements, beginning with single poses from docking, then including multiple poses, additional protein conformational changes, and using an improved charge model. Computed absolute binding free energies had an RMS error of 1.9 kcal/mol relative to previously determined experimental values. In blind prospective tests, the methods correctly discriminated between several true ligands and decoys in a set of putative binders identified by docking. In these prospective tests, the RMS error in predicted binding free energies relative to those subsequently determined experimentally was only 0.6 kcal/mol. X-ray crystal structures of the new ligands bound in the cavity corresponded closely to predictions from the free energy calculations, but sometimes differed from those predicted by docking. Finally, we examined the impact of holding the protein rigid, as in docking, with a view to learning how approximations made in docking affect accuracy and how they may be improved.
About this Structure
2OU0 is a Single protein structure of sequence from Enterobacteria phage t4. Full crystallographic information is available from OCA.
Reference
Predicting absolute ligand binding free energies to a simple model site., Mobley DL, Graves AP, Chodera JD, McReynolds AC, Shoichet BK, Dill KA, J Mol Biol. 2007 Aug 24;371(4):1118-34. Epub 2007 Jun 8. PMID:17599350 Page seeded by OCA on Sun May 4 11:39:01 2008
