2OU0

1-methylpyrrole in complex with T4 Lysozyme L99A

Summary for 2OU0

• Entry DOI: 10.2210/pdb2ou0/pdb
• Related: 181L
• Descriptor: Lysozyme, PHOSPHATE ION, 1-METHYL-1H-PYRROLE, ... (4 entities in total)
• Functional Keywords: hydrolase, protein-ligand complex, model system
• Biological source: Enterobacteria phage T4
• Cellular location: Host cytoplasm : P00720
• Total number of polymer chains: 1
• Total formula weight: 18711.20

Authors

Graves, A.P.,Shoichet, B.K. (deposition date: 2007-02-09, release date: 2007-08-07, Last modification date: 2023-08-30)

Primary citation

Mobley, D.L.,Graves, A.P.,Chodera, J.D.,McReynolds, A.C.,Shoichet, B.K.,Dill, K.A.
Predicting absolute ligand binding free energies to a simple model site.
J.Mol.Biol., 371:1118-1134, 2007

PubMed Abstract: 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.

PubMed: 17599350
DOI: 10.1016/j.jmb.2007.06.002

Experimental method

X-RAY DIFFRACTION (1.94 Å)