Computational Study for the Unbinding Routes of β-N-Acetyl-d-Hexosaminidase Inhibitor: Insight from Steered Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Results and Discussion
2.1. The Conformational Change of MD Simulation
2.2. Analysis of Unbinding Pathways by CAVER
2.3. SMD Simulations
2.4. PMFs during the Unbinding Route of TMG-Chitotriomycin
2.5. Important Residues during the Unbinding of the Ligand
2.6. The “Open–Close” Conformational Change of Glu368 and Trp448
3. Materials and Methods
3.1. Preparation of Starting Structure
3.2. MD Simulations
3.3. CAVER
3.4. SMD Simulations
- (1)
- The direction from the Cα atom of Tyr275 to the CAD atom of ligand (Figure 4, Route 1);
- (2)
- The direction from the Cα atom of Lys273 to the C7 atom of ligand (Figure 4, Route 2);
- (3)
- The direction from the Cα atom of Val500 to the CAZ atom of ligand (Figure 4, Route 3);
- (4)
- The direction from the Cα atom of Agr220 to the C5 atom of ligand (Figure 4, Route 4);
- (5)
- The direction from the Cα atom of Asp367 to the C1 atom of ligand (Figure 4, Route 5);
- (6)
- The direction from the Cα atom of Trp524 to the C1 atom of ligand (Figure 4, Route 6).
3.5. PMFs Calculation
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
OfHex1 | β-N-Acetyl-d-hexosaminidase from Ostrinia Furnacalis |
PMFs | Potential of mean forces |
MD | Molecular dynamics |
SMD | Steered molecular dynamics |
CMD1 | The first conventional molecular dynamics simulation |
CMD2 | The second conventional molecular dynamics simulation |
CMD3 | The third conventional molecular dynamics simulation |
RMSD | Root mean square deviation |
RMSFs | Root mean square fluctuations |
L478-496 | Loop residues 478-496 |
L314-355 | Loop residues 314-335 |
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Dissociation Routes | Average Radius | Average Length | Priority |
---|---|---|---|
Route 1 | 4.23 | 2.90 | 0.962 |
Route 2 | 3.30 | 9.14 | 0.906 |
Route 3 | 2.53 | 9.21 | 0.876 |
Route 4 | 2.34 | 19.51 | 0.806 |
Route 5 | 2.29 | 5.90 | 0.879 |
Route 6 | 1.35 | 15.65 | 0.730 |
Route | Residues | Probability (%) |
---|---|---|
1 | Tyr475 | 11 |
Trp490 | 14 | |
Glu368 | 11 | |
Trp448 | 14 | |
2 | Val484 | 10 |
Asn489 | 11 | |
Trp490 | 11 | |
Glu526 | 11 | |
Val327 | 11 | |
Glu328 | 10 | |
3 | Gly366 | 11 |
Glu368 | 14 | |
Thr425 | 14 | |
Ser426 | 14 | |
Thr427 | 13 | |
Trp448 | 14 | |
4 | Val327 | 19 |
Asp367 | 17 | |
Glu368 | 20 | |
Val369 | 14 | |
Ser370 | 13 | |
5 | Tyr471 | 23 |
Tyr475 | 14 | |
Trp490 | 27 | |
Trp448 | 27 | |
6 | Ala482 | 12 |
Gly485 | 11 | |
Gly487 | 10 | |
Asn488 | 11 | |
Trp483 | 9 | |
Val484 | 10 | |
Asn489 | 9 |
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Hu, S.; Zhao, X.; Zhang, L. Computational Study for the Unbinding Routes of β-N-Acetyl-d-Hexosaminidase Inhibitor: Insight from Steered Molecular Dynamics Simulations. Int. J. Mol. Sci. 2019, 20, 1516. https://doi.org/10.3390/ijms20061516
Hu S, Zhao X, Zhang L. Computational Study for the Unbinding Routes of β-N-Acetyl-d-Hexosaminidase Inhibitor: Insight from Steered Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2019; 20(6):1516. https://doi.org/10.3390/ijms20061516
Chicago/Turabian StyleHu, Song, Xiao Zhao, and Li Zhang. 2019. "Computational Study for the Unbinding Routes of β-N-Acetyl-d-Hexosaminidase Inhibitor: Insight from Steered Molecular Dynamics Simulations" International Journal of Molecular Sciences 20, no. 6: 1516. https://doi.org/10.3390/ijms20061516