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Thermodynamic resolution: How do errors in modeled protein structures affect binding affinity predictions?
Author(s) -
Singh Manoj Kumar,
Dominy Brian N.
Publication year - 2010
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.22691
Subject(s) - affinities , binding affinities , chemistry , binding site , ligand (biochemistry) , plasma protein binding , protein structure , crystallography , biophysics , stereochemistry , biology , biochemistry , receptor
The present study addresses the effect of structural distortion, caused by protein modeling errors, on calculated binding affinities toward small molecules. The binding affinities to a total of 300 distorted structures based on five different protein–ligand complexes were evaluated to establish a broadly applicable relationship between errors in protein structure and errors in calculated binding affinities. Relatively accurate protein models (less than 2 Å RMSD within the binding site) demonstrate a 14.78 (±7.5)% deviation in binding affinity from that calculated by using the corresponding crystal structure. For structures of 2–3 Å, 3–4 Å, and >4 Å RMSD within the binding site, the error in calculated binding affinity increases to 20.8 (±5.98), 22.79 (±11.3), and 29.43 (±11.47)%, respectively. The results described here may be used in combination with other tools to evaluate the utility of modeled protein structures for drug development or other ligand‐binding studies. Proteins 2010. © 2010 Wiley‐Liss, Inc.