2oty
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1,2-dichlorobenzene in complex with T4 Lysozyme L99A
OverviewOverview
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 StructureAbout this Structure
2OTY is a Single protein structure of sequence from Bacteriophage t4 with PO4, BME and YAN as ligands. Active as Lysozyme, with EC number 3.2.1.17 Full crystallographic information is available from OCA.
ReferenceReference
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 Wed Nov 21 13:18:44 2007