Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations
Abstract
:1. Introduction
2. Results and Discussion
2.1. Simulation System Integrity
2.2. Allosteric Na+ Binding
2.3. Transmembrane Helix and Loop Dynamics
2.4. Correlated Side-Chain Motions in the Transmembrane Domain
2.5. Intramolecular Interactions
2.6. Intermolecular Interactions
3. Methods
3.1. System Building
3.2. MD Simulations
3.3. MD Trajectory Analysis
3.4. Sequence Alignment and Conservation Analysis
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Residue | Frequency of Contact/% | |||||||
---|---|---|---|---|---|---|---|---|
Epinephrine-Bound β2AR | Ligand-Free β2AR | |||||||
Gs Protein Complex | β-Arrestin-2 Complex | Gs Protein Complex | β-Arrestin-2 Complex | |||||
Active | Inactive | Active | Inactive | Active | Inactive | Active | Inactive | |
D792.50 | 0.0 | 0.0 | 0.0 | 0.0 | 52.15 | 93.41 | 25.91 | 26.04 |
D1133.32 | <0.1 | 32.33 | 0.0 | 0.0 | 9.22 | 45.06 | 5.02 | 72.03 |
S1203.39 | 0.0 | 0.0 | 0.0 | 0.0 | 44.95 | 96.36 | 5.55 | 25.86 |
W2866.48 | 0.0 | 6.88 | 0.0 | 0.0 | 3.36 | 19.51 | 29.16 | 10.92 |
N3187.45 | 0.0 | 0.0 | 0.0 | 0.0 | 2.78 | 0.46 | 46.14 | 0.22 |
S3197.46 | 0.0 | 0.0 | 0.0 | 0.0 | 30.52 | 14.39 | 79.75 | 24.69 |
N3227.49 | 0.0 | 0.0 | 0.0 | 0.0 | 45.87 | 51.12 | 8.17 | 20.06 |
Y3267.53 | 0.0 | 0.0 | 0.0 | 0.0 | 0.12 | 0.60 | 0.0 | 0.0 |
Interactions | Residues Involved | Epinephrine-Bound | Ligand-Free | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Active State | Inactive State | Active State | Inactive State | |||||||||
Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | |||||
1 | 2 | 3 | Restrained | |||||||||
Salt Bridge | ||||||||||||
Intra-DRY | D1303.49; R1313.50 | 26.5 | 5.7 | 6.0 | 0 | 65.1 | 40.4 | 35.5 | 40.5 | 10.7 | 51.2 | 41.3 |
H-bonds | ||||||||||||
DRY-H8 | R1313.50; S3298.47 | 0.1 | 0 | 0.3 | 0 | 0.1 | 0 | 0 | 0.1 | 0.1 | 0.0 | 0.0 |
BP | D1133.32; Y3167.43 | 14.0 | 80.6 | 82.1 | 95.3 | 28.3 | 65.9 | 69.2 | 96.1 | 9.9 | 0.1 | 14.6 |
intra-DRY | D1303.49; R1313.50 | 65.9 | 64.5 | 17.9 | 16.8 | 35.7 | 80.0 | 72.9 | 82.3 | 30.5 | 99.8 | 83.5 |
DRY-ICL2 | D1303.49; Y141ICL2 | 99.3 | 97.5 | 92.4 | 98.0 | 99.8 | 0 | 0 | 98.1 | 86.2 | 0 | 0 |
D1303.49; S143ICL2; L144ICL2 | 0 | 0 | 0 | 0 | 0 | 99.5 | 90.8 | 0 | 0 | 0 | 37.3 | |
DRY-TM5 | R1313.50; Y2195.58 | 3.9 | 10.5 | 4.6 | 45.2 | 30.9 | 0 | 0 | 5.7 | 3.3 | 0 | 0 |
DRY-TM6 | R1313.50; E2686.30 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
CWxP-TM7 | C2856.47; W2866.48; N3187.45 | 1.8 | 3.4 | 45.1 | 4.1 | 5.3 | 11.7 | 4.3 | 17.6 | 0.5 | 53.7 | 3.8 |
Interactions | Residues Involved, Respectively | Epinephrine-Bound | Ligand-Free | |||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
Active State | Inactive State | Active State | Inactive State | |||||||||
Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | Gs Protein Complex | β-Arrestin-2 | |||||
1 | 2 | 3 | Restrained | |||||||||
Salt Bridge | ||||||||||||
BP-epi | D1133.32; epi | 67.5 | 51.0 | 4.8 | 52.7 | 36.0 | 29.3 | 60.1 | - | - | - | - |
H-bonds | ||||||||||||
BP-epi | D1133.32; epi | 96.7 | 96.0 | 8.3 | 99.3 | 55.5 | 53.8 | 93.3 | - | - | - | - |
H8-H5Gα | S329-L340; T369-L394 | 0.0 | 7.3 | 4.0 | 0.0 | - | 0.0 | - | 0.0 | - | 0.0 | - |
ICl1-H5Gα | F61-T66; T369-L394 | 0.2 | 0.1 | 0.0 | 0.2 | - | 0.6 | - | 30.3 | - | 40.0 | - |
ICl2-H5Gα | S137-T146; T369-L394 | 0.1 | 0.1 | 17.9 | 0.5 | - | 9.9 | - | 5.1 | - | 31.5 | - |
ICL3-H5Gα | E237-K267; T369-L394 | 90.5 | 92.5 | 97.5 | 96.3 | - | 77.1 | - | 76.2 | - | 76.7 | - |
H8-FL | S329-L340; G65-K78 | - | - | - | - | 33.4 | - | 0.0 | - | 0.0 | - | 0.0 |
ICl1-FL | F61-T66; G65-K78 | - | - | - | - | 25.6 | - | 58.8 | - | 22.9 | - | 49.3 |
ICL2-FL | S137-T146; G65-K78 | - | - | - | - | 8.7 | - | 30.4 | - | 77.8 | - | 35.6 |
ICL3-FL | E237-K267; G65-K78 | - | - | - | - | 85.5 | - | 71.7 | - | 14.8 | - | 14.0 |
H8-ML | S329-L340; P132-A140 | - | - | - | - | 0.0 | - | 0.0 | - | 0.0 | - | 0.0 |
ICL1-ML | F61-T66; P132-A140 | - | - | - | - | 0.9 | - | 0.1 | - | 0.0 | - | 0.0 |
ICL2-ML | S137-T146; P132-A140 | - | - | - | - | 7.1 | - | 4.2 | - | 9.3 | - | 30.3 |
ICL3-ML | E237-K267; P132-A140 | - | - | - | - | 0.0 | - | 0.0 | - | 0 | - | 0 |
H8-CL | S329-L340; V307-G317 | - | - | - | - | 0.0 | - | 0.0 | - | 0.0 | - | 0.0 |
ICl1-CL | F61-T66; V307-G317 | - | - | - | - | 0.0 | - | 0.0 | - | 0.0 | - | 0.0 |
ICL2-CL | S137-T146; V307-G317 | - | - | - | - | 4.6 | - | 58.4 | - | 0.2 | - | 8.9 |
ICL3-CL | E237-K267; V307-G317 | - | - | - | - | 0.0 | - | 0.0 | - | 4.0 | - | 0 |
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Mitra, A.; Sarkar, A.; Borics, A. Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations. Int. J. Mol. Sci. 2021, 22, 10423. https://doi.org/10.3390/ijms221910423
Mitra A, Sarkar A, Borics A. Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2021; 22(19):10423. https://doi.org/10.3390/ijms221910423
Chicago/Turabian StyleMitra, Argha, Arijit Sarkar, and Attila Borics. 2021. "Universal Properties and Specificities of the β2-Adrenergic Receptor-Gs Protein Complex Activation Mechanism Revealed by All-Atom Molecular Dynamics Simulations" International Journal of Molecular Sciences 22, no. 19: 10423. https://doi.org/10.3390/ijms221910423