Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study
Abstract
:1. Introduction
2. Results and Discussion
2.1. Modeling of the H2R in the Active State
2.2. Interface between the Receptor and the Gs Protein
- (i)
- (ii)
- As recently demonstrated for 2AR, transient interactions observed between the GPCR and GDP-bound Gs protein may represent an intermediate on the way to the formation of the final complex and may contribute to coupling specificity [53].
2.3. Conformational Stability of the Active H2R
3. Materials and Methods
3.1. Molecular Modeling of the H2R-Gs Complex
3.2. Overview of the Molecular Dynamics Simulations
3.3. Investigation of H2R Conformational Stability
3.4. Structural Analysis
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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System | Binding Energy [kcal/mol] |
---|---|
H-cMD1 | –13.13 ± 0.02 |
H-cMD2 | –13.09 ± 0.04 |
H-Gs-cMD1 | –14.36 ± 0.03 |
H-Gs-cMD2 | –13.87 ± 0.04 |
H-5-cMD1 | –13.41 ± 0.03 |
H-5-cMD2 | –11.76 ± 0.04 |
Simulation Name | Runs × Time | H2R | HSM | Gs | #Atoms | #Water | #DOPC | Water Box Dimensions |
---|---|---|---|---|---|---|---|---|
Deduction of histamine (HSM) binding mode | ||||||||
Multiple walker metadynamics | 32 × 48 ns | ✓ | ✓ | ✓ | 355,534 | 82,961 | 638 | 14.5 Å × 14.5 Å × 16.5 Å |
Refinement cMD cluster{1–5} | 5 × 1 s | ✓ | ✓ | ✓ | 355,534 | 82,961 | 638 | 14.5 Å × 14.5 Å × 16.5 Å |
Validation of stability and switchability | ||||||||
cMD{1–2} GaMD{1–5} | 7 × 1 s | ✓ | × | × | 125,620 | 27,519 | 278 | 9.6 Å × 9.7 Å × 13.0 Å |
H-cMD{1–2} H-GaMD{1–5} | 7 × 1 s | ✓ | ✓ | × | 125,638 | 27,519 | 278 | 9.6 Å × 9.7 Å × 13.0 Å |
H-Gs-cMD{1–2} H-Gs-GaMD{1–2} | 4 × 1 s | ✓ | ✓ | ✓ | 355,534 | 82,961 | 638 | 14.5 Å × 14.5 Å × 16.5 Å |
H-5-cMD{1–2} H-5-GaMD{1–2} | 4 × 1 s | ✓ | ✓ | ⋋ | 342,067 | 110,592 | 638 | 14.5 Å × 14.5 Å × 16.5 Å |
Simulation Name | Total E Boost [kcal/mol] | Dihedral Energy Boost [kcal/mol] |
---|---|---|
GaMD1 | 7.19 ± 3.11 | 6.61 ± 2.67 |
GaMD2 | 7.17 ± 3.06 | 6.56 ± 2.67 |
GaMD3 | 7.47 ± 3.16 | 6.72 ± 2.70 |
GaMD4 | 7.70 ± 3.19 | 6.63 ± 2.69 |
GaMD5 | 7.64 ± 3.16 | 6.05 ± 2.55 |
H-GaMD1 | 8.52 ± 3.48 | 6.24 ± 2.59 |
H-GaMD2 | 7.59 ± 3.18 | 5.94 ± 2.55 |
H-GaMD3 | 7.45 ± 3.14 | 6.26 ± 2.61 |
H-GaMD4 | 7.56 ± 3.22 | 6.16 ± 2.57 |
H-GaMD5 | 7.27 ± 3.10 | 6.15 ± 2.57 |
H-Gs-GaMD1 | 34.72 ± 6.85 | 6.68 ± 2.76 |
H-Gs-GaMD2 | 7.89 ± 3.56 | 7.51 ± 2.94 |
H-5-GaMD1 | 10.21 ± 4.39 | 6.68 ± 2.73 |
H-5-GaMD2 | 7.81 ± 4.00 | 6.87 ± 2.79 |
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Conrad, M.; Söldner, C.A.; Miao, Y.; Sticht, H. Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study. Int. J. Mol. Sci. 2020, 21, 6693. https://doi.org/10.3390/ijms21186693
Conrad M, Söldner CA, Miao Y, Sticht H. Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study. International Journal of Molecular Sciences. 2020; 21(18):6693. https://doi.org/10.3390/ijms21186693
Chicago/Turabian StyleConrad, Marcus, Christian A. Söldner, Yinglong Miao, and Heinrich Sticht. 2020. "Agonist Binding and G Protein Coupling in Histamine H2 Receptor: A Molecular Dynamics Study" International Journal of Molecular Sciences 21, no. 18: 6693. https://doi.org/10.3390/ijms21186693