title: Thermodynamic resolution: how do errors in modeled protein structures affect binding affinity predictions?
abstract: 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.
authors.affiliation: Department of Chemistry, Clemson University, Clemson, South Carolina 29634, USA.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Singh
authors.forename: Brian N
authors.initials: BN
authors.lastname: Dominy
mesh_terms: D018360:Crystallography, X-Ray; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D040681:Structural Homology, Protein; D013816:Thermodynamics
chemical_list: D011506:Proteins