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Predicting absolute ligand binding free energies to a simple model site.

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.

journal_name

J Mol Biol

journal_title

Journal of molecular biology

authors

Mobley DL,Graves AP,Chodera JD,McReynolds AC,Shoichet BK,Dill KA

doi

10.1016/j.jmb.2007.06.002

subject

Has Abstract

pub_date

2007-08-24 00:00:00

pages

1118-34

issue

4

eissn

0022-2836

issn

1089-8638

pii

S0022-2836(07)00776-0

journal_volume

371

pub_type

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