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

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 (EDIAm) 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, EDIAm 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.