Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling
Abstract
:1. Introduction
2. Results and Discussion
2.1. Structural Stability and Flexibility
2.2. Internal Dynamics of BRD9 Affected by Binding of 82I and POJ
2.3. Analyses of Markov Model
2.4. Binding Ability of Two Types of Inhibitors to BRD9
3. Materials and Methods
3.1. Preparation of Simulation Systems
3.2. Multiple Independent Molecular Dynamics Simulations
3.3. Markov Models
3.3.1. TICA Dimensionality Reduction Method
3.3.2. K-Means Clustering Algorithm
3.3.3. Determination of Lag Time
3.3.4. Flux Analysis
3.4. MM-GBSA Calculations
3.5. Solvated Interaction Energy Method
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pathways | Path Flux (s−1) | Percentage of Total Coarse Flux (%) |
---|---|---|
SA → S1 → SB | 2.09 × 10−4 | 98.9 |
SA → SB | 1.22 × 10−6 | 0.6 |
SA → S1 → S2 → SB | 1.20 × 10−6 | 0.6 |
Total | 2.11 × 10−4 | 100 |
Complex | 82I-BRD9 | POJ-BRD9 | 82I (ALL-BRD9) | POJ (ALL-BRD9) | ||||
---|---|---|---|---|---|---|---|---|
Average | Std | Average | Std | Average | Std | Average | Std | |
−10.96 | 6.42 | −21.51 | 17.71 | −9.27 | 7.60 | −22.60 | 16.56 | |
−23.37 | 5.20 | −27.77 | 8.52 | −18.50 | 8.54 | −30.66 | 9.30 | |
17.59 | 5.46 | 30.09 | 16.44 | 15.06 | 7.63 | 32.76 | 14.66 | |
−3.02 | 0.62 | −3.83 | 1.04 | −2.45 | 1.09 | −4.29 | 1.14 | |
6.63 | 5.94 | 8.58 | 17.08 | 5.79 | 7.62 | 10.16 | 15.61 | |
14.94 | 3.84 | 20.60 | 4.68 | 13.85 | 5.24 | 21.19 | 3.88 | |
−4.83 | −2.42 | −1.31 | −3.59 |
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Wang, B.; Wang, J.; Yang, W.; Zhao, L.; Wei, B.; Chen, J. Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling. Molecules 2024, 29, 3496. https://doi.org/10.3390/molecules29153496
Wang B, Wang J, Yang W, Zhao L, Wei B, Chen J. Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling. Molecules. 2024; 29(15):3496. https://doi.org/10.3390/molecules29153496
Chicago/Turabian StyleWang, Bin, Jian Wang, Wanchun Yang, Lu Zhao, Benzheng Wei, and Jianzhong Chen. 2024. "Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling" Molecules 29, no. 15: 3496. https://doi.org/10.3390/molecules29153496
APA StyleWang, B., Wang, J., Yang, W., Zhao, L., Wei, B., & Chen, J. (2024). Unveiling Allosteric Regulation and Binding Mechanism of BRD9 through Molecular Dynamics Simulations and Markov Modeling. Molecules, 29(15), 3496. https://doi.org/10.3390/molecules29153496