Thermodynamic resolution: how do errors in modeled protein structures affect binding affinity predictions?

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 A 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 A, 3-4 A, and >4 A 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.