Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation
Abstract
:1. Introduction
2. Results and Discussion
2.1. RMSD and RMSF Analysis
2.2. DCCM and PCA Analysis
2.3. MM/GBSA Free Energy Analysis
2.4. Superposition of the Wild Type and Mutation Structures
2.5. Allosteric Network Analysis
3. Materials and Methods
3.1. Construction of Simulation System
3.2. MD Simulations
3.3. Principal Component Analysis
3.4. Molecular Mechanics Generalized Born Surface Area Calculations
3.5. Dynamic Network Analysis
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Items | WT | R135K | Energy Difference |
---|---|---|---|
ΔEvdW b | −68.36 (4.36) | −61.57 (5.49) | 6.79 |
ΔEele c | −75.44 (31.88) | −37.60 (39.73) | 37.84 |
ΔEGB d | 97.24 (28.18) | 68.16 (35.80) | −29.08 |
ΔESURF e | −8.63 (0.57) | −7.46 (0.78) | 1.17 |
ΔGgas | −143.80 (32.67) | −99.17 (40.27) | 44.63 |
ΔGnonpolar | 97.37 (1.22) | 68.74 (10.14) | −28.63 |
ΔGpolar | −8.76 (0.13) | −8.04 (0.12) | 0.72 |
ΔGbinding | −55.19 (7.88) | −38.47 (8.56) | 16.72 |
Number | H Bonds or Salt Bridges | Distance (Å) | |
Hb1 | NS1-D30-OD2 | H-Ras-R135-NH2 | 3.75 |
Hb2 | NS1-E49-OE1 | H-Ras-R135-NE | 2.73 |
Hb3 | NS1-E49-OE2 | H-Ras-R135-NH1 | 2.89 |
Hb4 | NS1-Y82-OH | H-Ras-R135-NH2 | 2.91 |
Sb1 | NS1-D30-OD2 | H-Ras-R135-NH2 | 3.75 |
Sb2 | NS1-E49-OE1 | H-Ras-R135-NE | 2.73 |
Sb3 | NS1-E49-OE1 | H-Ras-R135-NH1 | 3.49 |
Sb4 | NS1-E49-OE2 | H-Ras-R135-NE | 3.67 |
Sb5 | NS1-E49-OE2 | H-Ras-R135-NH1 | 2.89 |
Number | Salt Bridges | Distance (Å) | |
Sb1 | NS1-E49-OE1 | H-Ras-K135-NZ | 3.76 |
Sb2 | NS1-E49-OE2 | H-Ras-K135-NZ | 3.96 |
Residue | WT | R135K | Energy Difference b | |
---|---|---|---|---|
NS1 | D29 | −3.25 (2.59) | −1.56 (2.39) | 1.69 |
Y30 | −3.02 (0.48) | −2.05 (0.77) | 0.97 | |
K44 | 1.24 (0.65) | 1.62 (1.39) | 0.38 | |
W72 | −6.02 (0.68) | −5.32 (0.73) | 0.70 | |
W74 | −2.11 (0.91) | −1.52 (0.88) | 0.59 | |
Y79 | −8.96 (0.87) | −8.04 (1.07) | 0.92 | |
H-Ras–GDP | R128 | −3.40 (2.33) | −1.15 (2.38) | 2.25 |
Q131 | −2.68 (1.36) | −2.01 (1.21) | 0.67 | |
R135K | −10.56 (1.94) | −2.75 (3.27) | 7.81 | |
I142 | −2.65 (0.76) | −2.34 (0.76) | 0.31 | |
E143 | −1.70 (1.09) | −0.94 (1.29) | 0.76 |
Pathway | Length a | Residue b | Subopt c | |||
---|---|---|---|---|---|---|
WT | R135K | WT | R135K | WT | R135K | |
R135(K)-R128 | 38 | 60 | 3 | 8 | 12 | 1 |
R135(K)-Q131 | 21 | 29 | 2 | 5 | 1 | 1 |
R135(K)-I142 | 68 | 61 | 4 | 8 | 9 | 0 |
R135(K)-E143 | 86 | 84 | 4 | 9 | 12 | 1 |
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Ni, D.; Song, K.; Zhang, J.; Lu, S. Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation. Int. J. Mol. Sci. 2017, 18, 2249. https://doi.org/10.3390/ijms18112249
Ni D, Song K, Zhang J, Lu S. Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation. International Journal of Molecular Sciences. 2017; 18(11):2249. https://doi.org/10.3390/ijms18112249
Chicago/Turabian StyleNi, Duan, Kun Song, Jian Zhang, and Shaoyong Lu. 2017. "Molecular Dynamics Simulations and Dynamic Network Analysis Reveal the Allosteric Unbinding of Monobody to H-Ras Triggered by R135K Mutation" International Journal of Molecular Sciences 18, no. 11: 2249. https://doi.org/10.3390/ijms18112249