Estimating Electron Density Support for Individual Atoms and Molecular Fragments in X-ray Structures

Abstract

Macromolecular structures resolved by X-ray crystallography are essential for life science research. While some methods exist to automatically quantify the quality of the electron density fit, none of them is without flaws. Especially the question of how well individual parts like atoms, small fragments, or molecules are supported by electron density is difficult to quantify. While taking experimental uncertainties correctly into account, they do not offer an answer on how reliable an individual atom position is. A rapid quantification of this atomic position reliability would be highly valuable in structure-based molecular design. To overcome this limitation, we introduce the electron density score EDIA for individual atoms and molecular fragments. EDIA assesses rapidly, automatically, and intuitively the fit of individual as well as multiple atoms (EDIA) into electron density accompanied by an integrated error analysis. The computation is based on the standard 2fo - fc electron density map in combination with the model of the molecular structure. For evaluating partial structures, EDIA shows significant advantages compared to the real-space R correlation coefficient (RSCC) and the real-space difference density Z score (RSZD) from the molecular modeler's point of view. Thus, EDIA abolishes the time-consuming step of visually inspecting the electron density during structure selection and curation. It supports daily modeling tasks of medicinal and computational chemists and enables a fully automated assembly of large-scale, high-quality structure data sets. Furthermore, EDIA scores can be applied for model validation and method development in computer-aided molecular design. In contrast to measuring the deviation from the structure model by root-mean-squared deviation, EDIA scores allow comparison to the underlying experimental data taking its uncertainty into account.

Validation of ligands in macromolecular structures determined by X-ray crystallography

“…The presence of difference electron density close to a ligand may be an indicator of subtle issues of ligand placement such as a chiral inversion or placement of a ring in a reversed orientation (Smart & Bricogne, 2015). Such difference density can be picked up by visual examination, but metrics that are sensitive to it, such as those provided by DDQ (van den Akker & Hol, 1999), EDSTATS (Tickle, 2012) or EDIAscorer (Meyder et al, 2017), need to be employed (Adams et al, 2016).…”

A New Clustering and Nomenclature for Beta Turns Derived from High-Resolution Protein Structures

“…We validated the new turn types by examining their electron density both visually and quantitatively. To analyze the electron density of atoms in beta turns, we utilized the EDIA program (Electron Density Support for Individual Atoms) [35], which integrates electron density in a sphere around each heavy atom and penalizes both positive and negative density in electron density difference maps. EDIA demonstrates that turns in each cluster contain only a few structures (0-2.4%) with substantial inconsistencies (Fig 4).…”

A 3D-QSAR Analysis of CDK2 Inhibitors Using FMO Calculations and PLS Regression

“…Here, the R-values and the DPI are the measures of the quality of the atomic model obtained from the crystallographic data. 17) A good atomic model has a value close to zero. The ligand EDIAm is an index for evaluating the goodness of fit of the ligand model with the electron density around the model.…”

“…The ligand EDIAm is an index for evaluating the goodness of fit of the ligand model with the electron density around the model. 18) A perfect fit would have a value of 1.2. The program DPICalc 19) was used for the DPI calculation and ProteinsPlus Server 20) was used for the EDIAm calculation.…”