'All That Glitters Is Not Gold': High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses.
Int J Mol Sci
; 22(13)2021 Jun 25.
Article
in English
| MEDLINE | ID: covidwho-1304663
ABSTRACT
Our understanding of the structure-function relationships of biomolecules and thereby applying it to drug discovery programs are substantially dependent on the availability of the structural information of ligand-protein complexes. However, the correct interpretation of the electron density of a small molecule bound to a crystal structure of a macromolecule is not trivial. Our analysis involving quality assessment of ~0.28 million small molecule-protein binding site pairs derived from crystal structures corresponding to ~66,000 PDB entries indicates that the majority (65%) of the pairs might need little (54%) or no (11%) attention. Out of the remaining 35% of pairs that need attention, 11% of the pairs (including structures with high/moderate resolution) pose serious concerns. Unfortunately, most users of crystal structures lack the training to evaluate the quality of a crystal structure against its experimental data and, in general, rely on the resolution as a 'gold standard' quality metric. Our work aims to sensitize the non-crystallographers that resolution, which is a global quality metric, need not be an accurate indicator of local structural quality. In this article, we demonstrate the use of several freely available tools that quantify local structural quality and are easy to use from a non-crystallographer's perspective. We further propose a few solutions for consideration by the scientific community to promote quality research in structural biology and applied areas.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Binding Sites
/
Proteins
/
Models, Molecular
/
Macromolecular Substances
/
Ligands
Type of study:
Experimental Studies
Language:
English
Year:
2021
Document Type:
Article
Affiliation country:
Ijms22136830
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