‘All That Glitters Is Not Gold’: High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses
Abstract
:1. Introduction
2. Results
2.1. General Analyses
2.2. Local Quality and Resolution
2.3. Case Studies
2.3.1. Case Study-1
VHELIBS and Visual Inspection
EDIA
PDB-REDO
Polder Maps
Ligand Building (with ARP/wARP)
Docking Simulations
2.3.2. Case Study-2
2.3.3. Case Study-3
2.4. In Silico Assessment of Stereochemical Features of P–L Complexes
3. Discussion
3.1. Sensitizing Users
3.2. Re-Visiting the Structures of Concern by Crystallographers
3.3. Proposals to the Journals
3.4. Proposals to the Repository Community
4. Materials and Methods
4.1. Dataset
4.2. Quality Assessment of Protein–Ligand Binding Sites
- (a)
- Maximum Real Space R-factor (RSR): 0.4;
- (b)
- Maximum ‘Good’ RSR: 0.24;
- (c)
- Minimum ‘Good’ real space correlation coefficient (RSCC): 0.9;
- (d)
- Average occupancy: 1.0;
- (e)
- Occupancy weighted average B-factor (OWAB): 50 Å2;
- (f)
- Maximum Rfree: 0.3;
- (g)
- Maximum [(Rfree) − (Rwork)] value: 0.05.
4.3. Polder Map Assessment
4.4. Ligand Building
4.5. Docking Simulation
4.6. Visualization and Graph Plotting
4.7. In Silico Approach to Assess Stereochemical Quality of P–L Binding Sites
4.8. Software Details
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Entity (Ligand/Residue) | VHELIBS * | EDIA Analysis | PDB Validation Report | |||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ligand Score; Binding Site Score; Category | EDIAm a | OPIA b | Mean B-Factor c | Occ. < 1.0 d | RSCC e | |||||||||||||||||||||||||
C1 | C2 | C3 | C4 $ | C17 | C1 | C2 | C3 | C4 | C17 | C1 | C2 | C3 | C4 | C17 | C1 | C2 | C3 | C4 | C17 | C1 | C2 | C3 | C4 | C17 | C1 | C2 | C3 | C4 | C17 | |
Ligand at S1 | 7;4; BB | 6;2; BD | 4;3; BB | NA | 5;3; BB | 0.22 | 0.38 | 0.39 | 0.27 | 0.41 | 0 | 15 | 36 | 14 | 0 | 75.01 (53.41) | 64.07 (32.05) | 19.96 (35.96) | 19.97 (39.87) | 82.52 (41.12) | 22 | 20 | 0 | 0 | 19 | 0.61 | 0.23 | 0.67 | 0.69 | 0.78 |
S1: Phe1 | NA | 0.56 | 0.90 | 0.81 | 0.69 | 0.70 | 27 | 91 | 73 | 36 | 36 | 56.53 | 29.01 | 35.90 | 45.28 | 38.92 | 0 | 0 | 0 | 0 | 0 | 0.93 | 0.93 | 0.95 | 0.94 | 0.95 | ||||
S1: Asn55 | NA | 0.74 | 0.67 | 0.70 | 0.67 | 0.54 | 75 | 50 | 75 | 63 | 38 | 59.71 | 41.85 | 38.72 | 46.98 | 53.29 | 0 | 0 | 0 | 0 | 0 | 0.87 | 0.87 | 0.86 | 0.79 | 0.94 | ||||
S1: Phe154 | NA | 0.79 | 0.77 | 0.73 | 0.80 | 0.68 | 73 | 55 | 55 | 45 | 45 | 57.93 | 37.09 | 43.20 | 45.71 | 55.62 | 0 | 0 | 0 | 0 | 0 | 0.90 | 0.93 | 0.93 | 0.93 | 0.94 | ||||
S1: Glu157 | NA | 0.36 | 0.35 | 0.70 | 0.55 | 0.76 | 44 | 56 | 56 | 44 | 44 | 54.83 | 32.04 | 36.58 | 38.39 | 35.86 | 3 | 3 | 3 | 3 | 0 | 0.96 | 0.96 | 0.94 | 0.93 | 0.98 | ||||
S1: Leu158 | NA | 0.63 | 0.90 | 0.76 | 0.82 | 0.79 | 75 | 75 | 75 | 75 | 75 | 51.19 | 29.96 | 31.86 | 35.88 | 29.28 | 0 | 0 | 0 | 0 | 0 | 0.96 | 0.98 | 0.98 | 0.96 | 0.93 | ||||
S1: Glu165 | NA | 0.87 | 0.84 | 0.91 | 0.91 | 0.84 | 56 | 56 | 78 | 89 | 67 | 57.10 | 36.72 | 41.59 | 47.95 | 38.21 | 0 | 0 | 0 | 0 | 0 | 0.91 | 0.95 | 0.96 | 0.96 | 0.92 | ||||
S1: Arg168 | NA | 0.38 | 0.33 | 0.33 | 0.26 | 0.59 | 45 | 36 | 36 | 36 | 45 | 60.94 | 45.93 | 45.71 | 56.23 | 62.37 | 6 | 6 | 6 | 6 | 1 | 0.96 | 0.94 | 0.94 | 0.92 | 0.93 | ||||
Ligand at S2 | 2;3; DB | 1;1; DD | 1;1; DD | 1;2; DD | 1;1; DD | 0.88 | 0.93 | 0.87 | 0.86 | 0.85 | 71 | 90 | 71 | 71 | 67 | 39.96 (44.30) | 23.01 (25.99) | 24.32 (29.96) | 24.14 (34.64) | 25.24 (29.73) | 0 | 0 | 0 | 0 | 0 | 0.94 | 0.95 | 0.98 | 0.97 | 0.97 |
Protein–Ligand Complex Identifier (Resolution) | VHELIBS * | EDIA Analysis | PDB Validation Report | PDB-REDO | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ligand Score; Binding Site Score; Category | EDIAm a | OPIA b | Mean B-Factor c | Occ. < 1.0 d | RSCC e | ΔRSCC f | ||||||||
SL | CSL | SL | CSL | SL | CSL | SL | CSL | SL | CSL | SL | CSL | SL | CSL | |
C5 (1.00 Å) | 4; 4; BB | 4; 4; BB | 0.10 | 0.08 | 0 | 0 | 63.29 (13.80) | 94.82 (14.32) | 0 | 0 | 0.62 | 0.32 | 0.281 (significant) | 0.226 (significant) |
C6 (1.10 Å) | 4; 3; BB | 3; 4; BB | 0.07 | 0.11 | 0 | 0 | 55.43 (9.72) | 63.60 (10.85) | 0 | 0 | 0.10 | 0.16 | 0.188 (significant) | 0.279 (significant) |
C7 (1.54 Å) | 4; 4; BB | 4; 4; BB | 0.24 | 0.18 | 0 | 0 | 71.94 (15.65) | 52.55 (16.45) | 0 | 0 | 0.14 | 0.34 | −0.016 (insignificant) | −0.017 (insignificant) |
C8 (1.78 Å) | 2; 3; DB | 3; 2; BD | 0.51 | 0.18 | 33 | 0 | 49.47 (14.40) | 49.78 (14.42) | 0 | 0 | 0.62 | 0.32 | −0.034 (insignificant) | −0.024 (insignificant) |
C9 (1.05 Å) | 2; 3; DB | 3; 2; BD | 0.04 | 0.1 | 0 | 0 | 55.04 (13.63) | 67.08 (14.27) | 0 | 0 | 0.37 | 0.12 | 0.153 (significant) | 0.240 (significant) |
C10 (1.08 Å) | N/A | 0; 0; GG | N/A | 0.84 | N/A | 73 | N/A | 5.5 (6.25) | N/A | 0 | N/A | N/A | N/A | 0.004 (significant) |
Protein–Ligand Complex Identifier; Ligand Code (Resolution) | VHELIBS * | EDIA Analysis | PDB Validation Report | PDB-REDO | |||
---|---|---|---|---|---|---|---|
Ligand Score; Binding Site Score; Category | EDIAm a | OPIA b | Mean B-factor c | Occ. < 1.0 d | RSCC e | ΔRSCC f | |
C11; L8 (3.4 Å) | 7; 6; BB | 0.23 | 6 | 79.20 (69.83) | 31 | 0.58 | 0.080 (insignificant) |
C12; L9 (3.4 Å) | 0; 3; GB | 0.88 | 81 | 106.33 (111.43) | 0 | 0.93 | 0.070 (insignificant) |
C13; L8 (3.4 Å) | 0; 3; BB | 0.74 | 61 | 109.38 (98.70) | 0 | 0.95 | 0.058 (significant) |
C14; L8 (3.4 Å) | 0; 2; GD | 0.84 | 77 | 47.55 (44.04) | 0 | 0.95 | −0.180 (significant) |
C15; L9 (3.4 Å) | 0; 1; GD | 0.72 | 56 | 49.71 (49.17) | 0 | 0.97 | −0.055 (significant) |
C16; L8 (2.1 Å) | 4; 1; BD | 0.31 | 19 | 61.20 (24.36) | 0 | 0.59 | 0.190 (significant) |
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Chakraborti, S.; Hatti, K.; Srinivasan, N. ‘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. 2021, 22, 6830. https://doi.org/10.3390/ijms22136830
Chakraborti S, Hatti K, Srinivasan N. ‘All That Glitters Is Not Gold’: High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses. International Journal of Molecular Sciences. 2021; 22(13):6830. https://doi.org/10.3390/ijms22136830
Chicago/Turabian StyleChakraborti, Sohini, Kaushik Hatti, and Narayanaswamy Srinivasan. 2021. "‘All That Glitters Is Not Gold’: High-Resolution Crystal Structures of Ligand-Protein Complexes Need Not Always Represent Confident Binding Poses" International Journal of Molecular Sciences 22, no. 13: 6830. https://doi.org/10.3390/ijms22136830