The good, the bad and the dubious: VHELIBS, a validation helper for ligands and binding sites

Abstract

BackgroundMany Protein Data Bank (PDB) users assume that the deposited structural models are of high quality but forget that these models are derived from the interpretation of experimental data. The accuracy of atom coordinates is not homogeneous between models or throughout the same model. To avoid basing a research project on a flawed model, we present a tool for assessing the quality of ligands and binding sites in crystallographic models from the PDB.ResultsThe Validation HElper for LIgands and Binding Sites (VHELIBS) is software that aims to ease the validation of binding site and ligand coordinates for non-crystallographers (i.e., users with little or no crystallography knowledge). Using a convenient graphical user interface, it allows one to check how ligand and binding site coordinates fit to the electron density map. VHELIBS can use models from either the PDB or the PDB_REDO databank of re-refined and re-built crystallographic models. The user can specify threshold values for a series of properties related to the fit of coordinates to electron density (Real Space R, Real Space Correlation Coefficient and average occupancy are used by default). VHELIBS will automatically classify residues and ligands as Good, Dubious or Bad based on the specified limits. The user is also able to visually check the quality of the fit of residues and ligands to the electron density map and reclassify them if needed.ConclusionsVHELIBS allows inexperienced users to examine the binding site and the ligand coordinates in relation to the experimental data. This is an important step to evaluate models for their fitness for drug discovery purposes such as structure-based pharmacophore development and protein-ligand docking experiments.

Models of protein–ligand crystal structures: trust, but verify

“…In the case of protein crystallography, the primary evidence is the electron density of the protein, ligand, and solvent molecules that form the crystal. The ability to conduct strict evidence-based validation has revealed a number of instances in which the ligands reported as bound to the protein are insufficiently supported by the primary evidence [12–14]. It is important to note that there may be other lines of evidence (e.g.…”

2-Methoxyestradiol Affects Mitochondrial Biogenesis Pathway and Succinate Dehydrogenase Complex Flavoprotein Subunit A in Osteosarcoma Cancer Cells

“…Crystal structure selection was based on the following criteria: high resolution of the crystal structure (below 3 Å) and electron density (ED) assessment. ED was evaluated using VHELIBS (32). The protein structure was obtained from the protein data bank (PDB) and Protein Preparation Wizard Maestro (Schrödinger) was used to add bond orders and hydrogen atoms to the crystal structure (33).…”

Improved ligand geometries in crystallographic refinement usingAFITTinPHENIX

“…Unfortunately, CIF-like restraints dictionaries are in widespread use today because they represent the same geometry restraints function as has been found to function well with protein residues. While PDB_Redo (Cereto- Massagué et al, 2013) has shown that improvements to the quality of the model can be made, we have shown that there is a limit, when using restraint dictionaries, to how much of an improvement can be made to ligand conformation energy and geometry. As a move is made to obtain more accurate models, it is our hope that refinement target functions will more often be implemented according to the paradigm presented here (Borbulevych, Plumley et al, 2014;Smart et al, 2010Smart et al, , 2014) so as to more accurately represent the complex conformational space of small-molecule ligands.…”