1,190
Views
3
CrossRef citations to date
0
Altmetric
Research Articles

A ‘deep dive’ into the SARS-Cov-2 polymerase assembly: identifying novel allosteric sites and analyzing the hydrogen bond networks and correlated dynamics

, , &
Pages 9443-9463 | Received 13 Jan 2021, Accepted 10 May 2021, Published online: 26 May 2021

References

  • Agostini, M. L., Andres, E. L., Sims, A. C., Graham, R. L., Sheahan, T. P., Lu, X., Smith, E. C., Case, J. B., Feng, J. Y., Jordan, R., Ray, A. S., Cihlar, T., Siegel, D., Mackman, R. L., Clarke, M. O., Baric, R. S., & Denison, M. R. (2018). Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio, 9(2). https://doi.org/10.1128/mBio.00221-18
  • Ahmed, M., & Barakat, K. (2017). The too many faces of PD-L1: a comprehensive conformational analysis study. Biochemistry, 56(40), 5428–5439. https://doi.org/10.1021/acs.biochem.7b00655
  • Appleby, T. C., Perry, J. K., Murakami, E., Barauskas, O., Feng, J., Cho, A., Fox, D., III; Wetmore, D. R., McGrath, M. E., Ray, A. S., Sofia, M. J., Swaminathan, S., & Edwards, T. E. (2015). Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase. Science, 347(6223), 771–775. https://doi.org/10.1126/science.1259210
  • Barakat, K. H., Anwar-Mohamed, A., Tuszynski, J. A., Robins, M. J., Tyrrell, D. L., & Houghton, M. (2014). A refined model of the HCV NS5A protein bound to daclatasvir explains drug-resistant mutations and activity against divergent genotypes. Journal of Chemical Information and Modeling. 55(2), 362–373.
  • Barakat, K. H., Huzil, J. T., Jordan, K. E., Evangelinos, C., Houghton, M., & Tuszynski, J. (2013). A computational model for overcoming drug resistance using selective dual-inhibitors for aurora kinase A and its T217D variant. Molecular Pharmaceutics, 10(12), 4572–4589. https://doi.org/10.1021/mp4003893
  • Barakat, K. H., Jordheim, L. P., Perez-Pineiro, R., Wishart, D., Dumontet, C., & Tuszynski, J. A. (2012). Virtual screening and biological evaluation of inhibitors targeting the XPA-ERCC1 interaction. PLoS One, 7(12), e51329. https://doi.org/10.1371/journal.pone.0051329
  • Barakat, K. H., Law, J., Prunotto, A., Magee, W. C., Evans, D. H., Tyrrell, D. L., Tuszynski, J., & Houghton, M. (2013). Detailed computational study of the active site of the hepatitis C viral RNA polymerase to aid novel drug design. Journal of Chemical Information and Modeling, 53(11), 3031–3043. https://doi.org/10.1021/ci4003969
  • Barakat, K., Issack, B. B., Stepanova, M., & Tuszynski, J. (2011). Effects of temperature on the p53-DNA binding interactions and their dynamical behavior: Comparing the wild type to the R248Q mutant. PLoS One, 6(11), e27651. https://doi.org/10.1371/journal.pone.0027651
  • Barakat, K., Mane, J., Friesen, D., & Tuszynski, J. (2010). Ensemble-based virtual screening reveals dual-inhibitors for the p53–MDM2/MDMX interactions. Journal of Molecular Graphics and Modelling, 28(6), 555–568. https://doi.org/10.1016/j.jmgm.2009.12.003
  • Beaulieu, P. L. (2009). Recent advances in the development of NS5B polymerase inhibitors for the treatment of hepatitis C virus infection. Expert Opinion on Therapeutic Patents, 19(2), 145–164. https://doi.org/10.1517/13543770802672598
  • Berendsen, H. J., Postma, J. V., van Gunsteren, W. F., DiNola, A., & Haak, J. (1984). Molecular dynamics with coupling to an external bath. The Journal of Chemical Physics, 81(8), 3684–3690. https://doi.org/10.1063/1.448118
  • Darden, T., York, D., & Pedersen, L. (1993). Particle mesh Ewald: An N⋅ log (N) method for Ewald sums in large systems. The Journal of Chemical Physics, 98(12), 10089–10092. https://doi.org/10.1063/1.464397
  • Davies, D. L., & Bouldin, D. W. (1979). A cluster separation measure. IEEE Transactions on Pattern Analysis and Machine Intelligence, PAMI-1(2), 224–227. https://doi.org/10.1109/TPAMI.1979.4766909
  • Dolinsky, T. J., Nielsen, J. E., McCammon, J. A., & Baker, N. A. (2004). PDB2PQR: An automated pipeline for the setup of Poisson-Boltzmann electrostatics calculations. Nucleic Acids Research, 32(Web Server), W665–W667. https://doi.org/10.1093/nar/gkh381
  • Elfiky, A. A. (2020). SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: An in silico perspective. Journal of Biomolecular Structure and Dynamics, 39(9), 3204–3212.
  • Ferrero, D., Ferrer-Orta, C., & Verdaguer, N. (2018). Viral RNA-dependent RNA polymerases: A structural overview. Subcell Biochemistry, 88, 39–71.
  • Ganta, N. M., Gedda, G., Rathnakar, B., Satyanarayana, M., Yamajala, B., Ahsan, M. J., Jadav, S. S., & Balaraju, T. (2019). A review on HCV inhibitors: Significance of non-structural polyproteins. European Journal of Medicinal Chemistry, 164, 576–601. https://doi.org/10.1016/j.ejmech.2018.12.045
  • Gao, Y., Yan, L., Huang, Y., Liu, F., Zhao, Y., Cao, L., Wang, T., Sun, Q., Ming, Z., Zhang, L., Ge, J., Zheng, L., Zhang, Y., Wang, H., Zhu, Y., Zhu, C., Hu, T., Hua, T., Zhang, B., … Rao, Z. (2020). Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science, 368(6492), 779–782. https://doi.org/10.1126/science.abb7498
  • Gedeon, P. C., Thomas, J. R., & Madura, J. D. (2015). Accelerated molecular dynamics and protein conformational change: A theoretical and practical guide using a membrane embedded model neurotransmitter transporter. Methods in Molecular Biology, 1215, 253–287.
  • Gordon, C. J., Tchesnokov, E. P., Feng, J. Y., Porter, D. P., & Gotte, M. (2020). The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. Journal of Biological Chemistry, 295(15), 4773–4779. https://doi.org/10.1074/jbc.AC120.013056
  • Gordon, C. J., Tchesnokov, E. P., Woolner, E., Perry, J. K., Feng, J. Y., Porter, D. P., & Gotte, M. (2020). Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. Journal of Biological Chemistry, 295(20), 6785–6797. https://doi.org/10.1074/jbc.RA120.013679
  • Graepel, K. W., Agostini, M. L., Lu, X., Sexton, N. R., & Denison, M. R. (2019). Fitness barriers limit reversion of a proofreading-deficient coronavirus. Journal of Virology, 93(20). https://doi.org/10.1128/JVI.00711-19
  • Grant, B. J., Rodrigues, A. P., ElSawy, K. M., McCammon, J. A., & Caves, L. S. (2006). Bio3d: An R package for the comparative analysis of protein structures. Bioinformatics, 22(21), 2695–2696. https://doi.org/10.1093/bioinformatics/btl461
  • Grindon, C., Harris, S., Evans, T., Novik, K., Coveney, P., & Laughton, C. (2004). Large-scale molecular dynamics simulation of DNA: Implementation and validation of the AMBER98 force field in LAMMPS. Philosophical Transactions of the Royal Society A Mathematical Physical and Engineering Science, 362(1820), 1373–1386. https://doi.org/10.1098/rsta.2004.1381
  • Hamelberg, D., Mongan, J., & McCammon, J. A. (2004). Accelerated molecular dynamics: A promising and efficient simulation method for biomolecules. The Journal of Chemical Physics, 120(24), 11919–11929. https://doi.org/10.1063/1.1755656
  • Hao, W., Wojdyla, J. A., Zhao, R., Han, R., Das, R., Zlatev, I., Manoharan, M., Wang, M., & Cui, S. (2017). Crystal structure of Middle East respiratory syndrome coronavirus helicase. PLoS Pathogens, 13(6), e1006474. https://doi.org/10.1371/journal.ppat.1006474
  • Hornak, V., Abel, R., Okur, A., Strockbine, B., Roitberg, A., & Simmerling, C. (2006). Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins, 65(3), 712–725. https://doi.org/10.1002/prot.21123
  • http://www.ks.uiuc.edu/Research/vmd/.
  • Huang, J., Song, W., Huang, H., & Sun, Q. (2020). Pharmacological therapeutics targeting RNA-dependent RNA polymerase, proteinase and spike protein: From mechanistic studies to clinical trials for COVID-19. Journal of Clinical Medicine, 9(4).
  • Humphrey, W., Dalke, A., & Schulten, K. (1996). VMD: Visual molecular dynamics. Journal of Molecular Graphics, 14(1), 33–38, 27–28. https://doi.org/10.1016/0263-7855(96)00018-5
  • Imbert, I., Guillemot, J. C., Bourhis, J. M., Bussetta, C., Coutard, B., Egloff, M. P., Ferron, F., Gorbalenya, A. E., & Canard, B. (2006). A second, non-canonical RNA-dependent RNA polymerase in SARS coronavirus. The EMBO Journal, 25(20), 4933–4942. https://doi.org/10.1038/sj.emboj.7601368
  • Jordheim, L. P., Barakat, K. H., Heinrich-Balard, L., Matera, E.-L., Cros-Perrial, E., Bouledrak, K., El Sabeh, R., Perez-Pineiro, R., Wishart, D. S., & Cohen, R. (2013). Small molecule inhibitors of ERCC1-XPF protein-protein interaction synergize alkylating agents in cancer cells. Molecular Pharmacology, 84(1), 12–24. https://doi.org/10.1124/mol.112.082347
  • Kokh, D. B., Richter, S., Henrich, S., Czodrowski, P., Rippmann, F., & Wade, R. C. (2013). TRAPP: A tool for analysis of transient binding pockets in proteins. Journal of Chemical Information and Modeling, 53(5), 1235–1252. https://doi.org/10.1021/ci4000294
  • Konecny, R., Baker, N. A., & McCammon, J. A. (2012). iAPBS: A programming interface to Adaptive Poisson-Boltzmann Solver (APBS). Computational Science & Discovery, 5(1).
  • Le Guilloux, V., Schmidtke, P., & Tuffery, P. (2009). Fpocket: An open source platform for ligand pocket detection. BMC Bioinformatics, 10, 168. https://doi.org/10.1186/1471-2105-10-168
  • Lehmann, K. C., Gulyaeva, A., Zevenhoven-Dobbe, J. C., Janssen, G. M., Ruben, M., Overkleeft, H. S., van Veelen, P. A., Samborskiy, D. V., Kravchenko, A. A., Leontovich, A. M., Sidorov, I. A., Snijder, E. J., Posthuma, C. C., & Gorbalenya, A. E. (2015). Discovery of an essential nucleotidylating activity associated with a newly delineated conserved domain in the RNA polymerase-containing protein of all nidoviruses. Nucleic Acids Research, 43(17), 8416–8434. https://doi.org/10.1093/nar/gkv838
  • Li, H., & Shi, S. T. (2010). Non-nucleoside inhibitors of hepatitis C virus polymerase: Current progress and future challenges. Future Medicinal Chemistry, 2(1), 121–141. https://doi.org/10.4155/fmc.09.148
  • Ma, Y., Wu, L., Shaw, N., Gao, Y., Wang, J., Sun, Y., Lou, Z., Yan, L., Zhang, R., & Rao, Z. (2015). Structural basis and functional analysis of the SARS coronavirus nsp14-nsp10 complex. Proceedings of the National Academy of Science of the United States of America, 112(30), 9436–9441. https://doi.org/10.1073/pnas.1508686112
  • Markwick, P. R. L., & McCammon, J. A. (2011). Studying functional dynamics in bio-molecules using accelerated molecular dynamics. Physical Chemistry Chemical Physics, 13(45), 20053–20065. https://doi.org/10.1039/c1cp22100k
  • Neogi, U., Hill, K. J., Ambikan, A. T., Heng, X., Quinn, T. P., Byrareddy, S. N., Sonnerborg, A., Sarafianos, S. G., & Singh, K. (2020). Feasibility of known RNA polymerase inhibitors as anti-SARS-CoV-2 drugs. Pathogens, 9(5), 320. https://doi.org/10.3390/pathogens9050320
  • Ryckaert, J.-P., Ciccotti, G., & Berendsen, H. J. C. (1977). Numerical integration of the cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. Journal of Computational Physics, 23(3), 327–341. https://doi.org/10.1016/0021-9991(77)90098-5
  • Shannon, A., Le, N. T., Selisko, B., Eydoux, C., Alvarez, K., Guillemot, J. C., Decroly, E., Peersen, O., Ferron, F., & Canard, B. (2020). Remdesivir and SARS-CoV-2: Structural requirements at both nsp12 RdRp and nsp14 Exonuclease active-sites. Antiviral Research, 178, 104793. https://doi.org/10.1016/j.antiviral.2020.104793
  • Shao, J., Tanner, S. W., Thompson, N., & Cheatham, T. E. (2007). Clustering molecular dynamics trajectories: 1. Characterizing the performance of different clustering algorithms. Journal of Chemical Theory and Computation, 3(6), 2312–2334. https://doi.org/10.1021/ct700119m
  • Snijder, E. J., Decroly, E., & Ziebuhr, J. (2016). The nonstructural proteins directing coronavirus RNA synthesis and processing. Advances in Virus Research, 96, 59–126.
  • Stank, A., Kokh, D. B., Horn, M., Sizikova, E., Neil, R., Panecka, J., Richter, S., & Wade, R. C. (2017). TRAPP webserver: Predicting protein binding site flexibility and detecting transient binding pockets. Nucleic Acids Research, 45(W1), W325–W330. https://doi.org/10.1093/nar/gkx277
  • Te Velthuis, A. J., Arnold, J. J., Cameron, C. E., van den Worm, S. H., & Snijder, E. J. (2010). The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids Research, 38(1), 203–214. https://doi.org/10.1093/nar/gkp904
  • Vilar, S., Cozza, G., & Moro, S. (2008). Medicinal chemistry and the molecular operating environment (MOE): Application of QSAR and molecular docking to drug discovery. Current Topics in Medicinal Chemistry, 8(18), 1555–1572. https://doi.org/10.2174/156802608786786624
  • Wang, J., Wang, W., Kollman, P. A., & Case, D. A. (2006). Automatic atom type and bond type perception in molecular mechanical calculations. Journal of Molecular Graphics and Modelling, 25(2), 247–260. https://doi.org/10.1016/j.jmgm.2005.12.005
  • Yang, J., Roy, A., & Zhang, Y. (2013). Protein-ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment. Bioinformatics, 29(20), 2588–2595. https://doi.org/10.1093/bioinformatics/btt447
  • Yin, W., Mao, C., Luan, X., Shen, D. D., Shen, Q., Su, H., Wang, X., Zhou, F., Zhao, W., Gao, M., Chang, S., Xie, Y. C., Tian, G., Jiang, H. W., Tao, S. C., Shen, J., Jiang, Y., Jiang, H., Xu, Y., … Xu, H. E. (2020). Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, 368(6498), 1499–1504. https://doi.org/10.1126/science.abc1560
  • Yuan, J. H., Han, S. B., Richter, S., Wade, R. C., & Kokh, D. B. (2020). Druggability assessment in TRAPP using machine learning approaches. Journal of Chemical Information and Modeling, 60(3), 1685–1699. https://doi.org/10.1021/acs.jcim.9b01185
  • Zhang, F., Yuan, Y., Li, H., Shen, L., Guo, Y., Wen, Z., & Pu, X. (2018). Using accelerated molecular dynamics simulation to shed light on the mechanism of activation/deactivation upon mutations for CCR5. RSC Advances, 8(66), 37855–37865. https://doi.org/10.1039/C8RA07686C
  • Zhou, P., Yang, X. L., Wang, X. G., Hu, B., Zhang, L., Zhang, W., Si, H. R., Zhu, Y., Li, B., Huang, C. L., Chen, H. D., Chen, J., Luo, Y., Guo, H., Jiang, R. D., Liu, M. Q., Chen, Y., Shen, X. R., Wang, X., … Shi, Z. L. (2020). A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature, 579(7798), 270–273. https://doi.org/10.1038/s41586-020-2012-7
  • Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G. F., & Tan, W. (2020). China novel coronavirus. I. A novel coronavirus from patients with pneumonia in China, 2019. New England Journal of Medicine, 382(8), 727–733. https://doi.org/10.1056/NEJMoa2001017

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.