The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19
Abstract
:1. Introduction
2. Methods and Results
2.1. SARS-CoV-2 RdRp Catalytic Chamber
Mapping and Characterization of the Two Binding Pockets, BS1 and BS2
3. Structural Architecture of BS1 and BS2
4. Hydrophobicity/Hydrophilicity Profiles of BS1 and BS2
5. BS1 and BS2 Binding Pocket Per-Residue Contribution Using Suramin as a Prototype
6. System Preparation and Molecular Dynamic Simulation
7. Dynamic Conformational Stability and Fluctuations
8. Binding Free Energy Calculations
9. Assessment of Comparative Binding Energies
10. 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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Site | Site Score | Size | Volume A3 | Dscore | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/acc |
---|---|---|---|---|---|---|---|---|---|---|---|
BS1 | 1.030 | 129 | 276.458 | 0.943 | 0.522 | 0.743 | 1.027 | 0.252 | 1.357 | 0.186 | 0.370 |
BS2 | 0.976 | 226 | 646.898 | 0.940 | 0.695 | 0.662 | 0.771 | 0.286 | 1.219 | 0.235 | 0.866 |
BS1/Suramin Complex | BS2/Suramin Complex | ||
---|---|---|---|
BS1 per-residue energy contribution | BS2 per-residue energy contribution | ||
Residue | Energy (kcal/mol) | Residue | Energy (kcal/mol) |
Asn496 | −22.51 | Arg555 | −30.26 |
Ile494 | −22.51 | Arg836 | −19.47 |
Arg569 | −19.44 | Arg553 | −13.50 |
Lys577 | −16.14 | LIe548 | −11.90 |
Gly590 | −15.77 | Ser549 | −11.19 |
Lys500 | −14.60 | Lys551 | −11.01 |
Gln573 | −8.99 | His439 | −10.08 |
Ala558 | −7.89 | Gly852 | −8.93 |
Ile589 | −7.01 | Arg858 | −5.84 |
Leu576 | −6.80 | Ala550 | −5.81 |
Asn497 | −6.48 | Ala840 | −5.48 |
Ala685 | −4.61 | Phe480 | −5.18 |
Systems | Estimated Averages (Å) | ||
---|---|---|---|
Ligand | RMSD | RMSF | SASA |
Remdesivir-BS1 | 1.58 | 1.06 | 14,011.99 |
Sofosbuvir-BS1 | 2.04 | 1.12 | 14,510.63 |
Alovudine-BS1 | 1.34 | 1.03 | 13,772.77 |
Molnupiravir-BS1 | 1.65 | 1.09 | 13,800.19 |
Zidovudine-BS1 | 1.72 | 1.08 | 13,706.09 |
Favilavir-BS1 | 1.57 | 1.17 | 14,271.97 |
Ribavirin-BS1 | 1.53 | 1.04 | 14,116.37 |
Suramin-BS1 | 1.62 | 1.20 | 13,911.23 |
Systems | Estimated Averages (Å) | ||
---|---|---|---|
Ligand | RMSD | RMSF | SASA |
Remdesivir-BS2 | 1.87 | 1.14 | 11,018.38 |
Sofosbuvir-BS2 | 2.09 | 1.35 | 11,193.50 |
Alovudine-BS2 | 1.80 | 1.06 | 10,655.36 |
Molnupiravir-BS2 | 2.13 | 1.21 | 11,180.05 |
Zidovudine-BS2 | 2.12 | 1.22 | 11,245.66 |
Favilavir-BS2 | 1.64 | 1.20 | 10,948.94 |
Ribavirin- BS2 | 1.68 | 1.11 | 11,244.42 |
Suramin-BS2 | 1.78 | 1.24 | 11,142.55 |
Systems | Energy Components | ||||
---|---|---|---|---|---|
(kcal/mol) | |||||
Ligand | ΔEvdw | ΔEele | ΔGgas | ΔGsol | ΔGbind |
Remdesivir-BS1 | −41.9522 | −335.8092 | −377.7613 | 325.1969 | −52.5645 |
Remdesivir-BS2 | −42.7075 | −90.9436 | −133.6512 | 109.1042 | −24.5469 |
Sofosbuvir-BS1 | −34.6272 | −15.0141 | −49.6413 | 25.2979 | −24.3434 |
Sofosbuvir-BS2 | −32.0037 | −19.3497 | −51.3534 | 33.6064 | −17.7470 |
Alovudine-BS1 | −21.7154 | −8.8406 | −30.5559 | 13.5672 | −16.9888 |
Alovudine-BS2 | −19.2905 | 3.337 | −15.9536 | 5.5781 | −10.3754 |
Molnupiravir-BS1 | −22.4816 | −34.6077 | −57.0892 | 43.4611 | −13.6282 |
Molnupiravir-BS2 | −26.1253 | −24.0320 | −56.1573 | 35.6699 | −14.4874 |
Zidovudine-BS1 | −24.3850 | −31.0102 | −57.3952 | 40.5715 | −14.8237 |
Zidovudine-BS2 | −15.3793 | −193.9331 | −209.3124 | 198.1934 | −11.1190 |
Favilavir-BS1 | −7.5696 | −37.4859 | −79.4035 | 90.7847 | −11.3812 |
Favilavir-BS2 | −7.3014 | −28.6874 | −72.1635 | 85.046 | −12.8825 |
Ribavirin-BS1 | −8.5964 | −20.8937 | −63.3037 | 76.6451 | −13.3414 |
Ribavirin-BS2 | −7.7187 | −27.1752 | −69.8784 | 83.4503 | −13.5719 |
Suramin-BS1 | −8.6775 | −48.0019 | −89.7680 | 102.9012 | −13.1331 |
Suramin-BS2 | −7.7503 | −51.9245 | −94.8926 | 107.5886 | −12.6959 |
All energies are in kcal/mol. | ΔEele = electrostatic energy | ΔEvdw = van der Waals energy | ΔGbind = total binding free energy | ΔGsol = solvation free energy | ΔG = gas phase free energy |
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Metwally, K.; Abo-Dya, N.E.; Alahmdi, M.I.; Albalawi, M.Z.; Yahya, G.; Aljoundi, A.; Salifu, E.Y.; Elamin, G.; Ibrahim, M.A.A.; Sayed, Y.; et al. The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19. Molecules 2023, 28, 2806. https://doi.org/10.3390/molecules28062806
Metwally K, Abo-Dya NE, Alahmdi MI, Albalawi MZ, Yahya G, Aljoundi A, Salifu EY, Elamin G, Ibrahim MAA, Sayed Y, et al. The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19. Molecules. 2023; 28(6):2806. https://doi.org/10.3390/molecules28062806
Chicago/Turabian StyleMetwally, Kamel, Nader E. Abo-Dya, Mohammed Issa Alahmdi, Maha Z. Albalawi, Galal Yahya, Aimen Aljoundi, Elliasu Y. Salifu, Ghazi Elamin, Mahmoud A. A. Ibrahim, Yasien Sayed, and et al. 2023. "The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)’s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19" Molecules 28, no. 6: 2806. https://doi.org/10.3390/molecules28062806