Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib
Abstract
:1. Introduction
2. Results and Discussion
2.1. Binding Mode of Trametinib to MEK1
2.2. Conformational Changes for Trametinib Bound to the WT MEK1 and Three Mutants
2.3. Structural Motion of the WT and Mutants MEK1 after Binding with Trametinib
2.4. CAVER 3.0 Identifies the Allosteric Channel of MEK1
2.5. Dissociation of Trametinib from the WT MEK1 and Its Three Mutants
3. Methods
3.1. Preparation of the Protein Structures
3.2. Docking Study
3.3. MD Simulations
3.4. Protein Structure Network Analysis
3.5. Cross Correlation Analysis and Principal Component Analysis (PCA)
3.6. MM-PBSA Calculations
3.7. Steered Molecular Dynamics Simulations
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
References
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System | Probability for α_Helix (%) | Probability for 310_Helix (%) |
---|---|---|
N214-I216 | P193-N195 | |
WT | 54.6 | 62.0 |
A52V | 94.7 | 79.6 |
E203K | 2.8 | 17.1 |
P124S | 8.8 | 44.2 |
Hydrogen Bonds | WT (%) | A52V (%) | P124S (%) | E203K (%) | |
---|---|---|---|---|---|
Donor | Accepter | ||||
Gly210:N | MOL:F34 | 81.8 ± 0.4 | 81.0 ± 0.4 | 23.9 ± 0.4 | 67.4 ± 0.5 |
Gly213:N | MOL:C10 | 40.8 ± 0.5 | 44.5 ± 0.5 | -- | -- |
Val211:N | MOL:O8 | 84.0 ± 0.4 | 80.9 ± 0.4 | 21.1 ± 0.4 | 79.6 ± 0.4 |
Ser212:N | MOL:O8 | 91.4 ± 0.3 | 81.4 ± 0.4 | 23.7 ± 0.4 | -- |
Ser212:OG | MOL:O8 | 58.4 ± 0.5 | 80.5 ± 0.4 | 45.9 ± 0.5 | 22.2 ± 0.4 |
Ser212:CB | MOL:O8 | 77.0 ± 0.4 | 62.5 ± 0.5 | 37.1 ± 0.5 | -- |
Ser212:OG | MOL:C7 | 81.9 ± 0.4 | 73.3 ± 0.4 | 33.4 ± 0.5 | 58.6 ± 0.5 |
Lys97:NZ | MOL:O12 | 71.6 ± 0.5 | 86.8 ± 0.3 | 65.3 ± 0.5 | 46.3 ± 0.5 |
Phe209:N | MOL:F34 | 37.9 ± 0.5 | 47.4 ± 0.5 | 26.0 ± 0.4 | -- |
Lys97:CD | MOL:O12 | 72.6 ± 0.4 | 40.8 ± 0.5 | 20.4 ± 0.4 | 39.3 ± 0.5 |
Lys97:CE | MOL:O12 | 66.6 ± 0.5 | 32.7 ± 0.5 | 23.4 ± 0.4 | 37.6 ± 0.5 |
Gly210:CA | MOL:F34 | 73.1 ± 0.4 | 66.9 ± 0.5 | -- | 41.9 ± 0.5 |
MOL:C35 | Asp208:N | 31.6 ± 0.5 | 20.8 ± 0.4 | -- | -- |
Val211:N | MOL:F34 | -- | 36.1 ± 0.5 | -- | -- |
Ser212:CA | MOL:O8 | 81.9 ± 0.4 | 73.5 ± 0.4 | -- | 28.9 ± 0.5 |
MOL:N22 | His100:O | 35.7 ± 0.5 | 24.5 ± 0.4 | -- | -- |
Asp208:N | MOL:C36 | 36.3 ± 0.5 | 36.6 ± 0.5 | -- | -- |
System | WT | A52V | P124S | E203K |
---|---|---|---|---|
ΔEele | −85.0 ± 10.4 | −87.9 ± 8.3 | −70.0 ± 7.5 | −69.9 ± 6.2 |
ΔEvdw | −54.6 ± 4.9 | −51.7 ± 4.7 | −41.0 ± 3.0 | −43.7 ± 3.9 |
ΔGnp | −5.6 ± 2.0 | −5.4 ± 1.6 | −4.8 ± 2.2 | −5.0 ± 1.7 |
ΔGpb | 90.1 ± 13.6 | 93.2 ± 12.1 | 75.1 ± 10.8 | 76.5 ± 15.3 |
TΔS | −60.2 ± 5.5 | −59.1 ± 4.9 | −45.9 ± 3.4 | −48.7 ± 3.2 |
ΔGbind | −55.0 ± 3.9 | −53.9 ± 2.5 | −40.7 ± 2.1 | −42.2 ± 3.3 |
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Zhu, J.; Li, C.; Yang, H.; Guo, X.; Huang, T.; Han, W. Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib. Int. J. Mol. Sci. 2020, 21, 2167. https://doi.org/10.3390/ijms21062167
Zhu J, Li C, Yang H, Guo X, Huang T, Han W. Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib. International Journal of Molecular Sciences. 2020; 21(6):2167. https://doi.org/10.3390/ijms21062167
Chicago/Turabian StyleZhu, Jingxuan, Congcong Li, Hengzheng Yang, Xiaoqing Guo, Tianci Huang, and Weiwei Han. 2020. "Computational Study on the Effect of Inactivating/Activating Mutations on the Inhibition of MEK1 by Trametinib" International Journal of Molecular Sciences 21, no. 6: 2167. https://doi.org/10.3390/ijms21062167