TY - JOUR
T1 - ‘All That Glitters Is Not Gold'
T2 - High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses
AU - Chakraborti, Sohini
AU - Hatti, Kaushik
AU - Srinivasan, Narayanaswamy
N1 - Funding Information:
Funding: Research in our group is generally supported by the FIST program sponsored by the Department of Science and Technology (DST) and the Department of Biotechnology (DBT), Government of India in the forms of the IISc-DBT partnership program and Bioinformatics and Computational Biology Centre. Support from UGC, India—Centre for Advanced Studies and Ministry of Human Resource Development, India, is gratefully acknowledged. S.C. is supported by the DST-INSPIRE research fellowship. N.S. is a J.C. Bose National Fellow.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/25
Y1 - 2021/6/25
N2 - 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.
AB - 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.
KW - Binding pose
KW - Electron density map
KW - Ligand–protein crystal structures
KW - PDB
KW - Quality assessment
KW - Resolution
UR - http://www.scopus.com/inward/record.url?scp=85108456478&partnerID=8YFLogxK
U2 - 10.3390/ijms22136830
DO - 10.3390/ijms22136830
M3 - Article
C2 - 34202053
AN - SCOPUS:85108456478
SN - 1661-6596
VL - 22
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 13
M1 - 6830
ER -