Advertisement

Biochemistry (Moscow)

, Volume 81, Issue 13, pp 1579–1588 | Cite as

Investigation of ribosomes using molecular dynamics simulation methods

  • G. I. Makarov
  • T. M. Makarova
  • N. V. Sumbatyan
  • A. A. BogdanovEmail author
Review

Abstract

The ribosome as a complex molecular machine undergoes significant conformational changes while synthesizing a protein molecule. Molecular dynamics simulations have been used as complementary approaches to X-ray crystallography and cryoelectron microscopy, as well as biochemical methods, to answer many questions that modern structural methods leave unsolved. In this review, we demonstrate that all-atom modeling of ribosome molecular dynamics is particularly useful in describing the process of tRNA translocation, atomic details of behavior of nascent peptides, antibiotics, and other small molecules in the ribosomal tunnel, and the putative mechanism of allosteric signal transmission to functional sites of the ribosome.

Keywords

ribosome molecular dynamics simulations allosteric signal transmission 

Abbreviations

MD

molecular dynamics

NPET

nascent peptide exit tunnel

PTC

peptidyl transferase center of the ribosome

REMD

replica exchange molecular dynamics

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Melnikov, S., Ben-Shem, A., Garreau de Loubresse, N., Jenner, L., Yusupova, G., and Yusupov, M. (2012) One core, two shells: bacterial and eukaryotic ribosomes, Nat. Struct. Mol. Biol., 19, 560–567.CrossRefPubMedGoogle Scholar
  2. 2.
    Amunts, A., Brown, A., Toots, J., Scheres, S. H. W., and Ramakrishnan, V. (2015) The structure of human mitochondrial ribosome, Science, 348, 95–98.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Frank, J. (2016) Whither ribosome structure and dynamics research? (A perspective), J. Mol. Biol., 428, 3565–3569.CrossRefPubMedGoogle Scholar
  4. 4.
    Wang, L., Pulk, A., Wasserman, M. R., Feldman, M. B., Altman, R. B., Doudna, C. J. H., and Blanchard, S. C. (2012) Allosteric control of the ribosome by small-molecule antibiotics, Nat. Struct. Mol. Biol., 19, 957–963.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Fei, J., Bronson, J. E., Hofman, J. M., Srinivas, R. L., Wiggins, C. H., and Gonzalez, R. L., Jr. (2009) Allosteric collaboration between elongation factor G and the ribosomal L1 stalk directs tRNA movements during translation, Proc. Natl. Acad. Sci. USA, 106, 15702–15707.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Sonbonmatsu, K. Y. (2012) Computational studies of molecular machines: ribosomes, Curr. Opin. Struct. Biol., 22, 168–174.CrossRefGoogle Scholar
  7. 7.
    Perilla, J. R., Goh, B. C., Cassidy, C. K., Liu, B., Bernardi, R. C., Rudack, T., Yu, H., Wu, Z., and Schulten, K. (2015) Molecular dynamics simulations of large macromolecular complexes, Curr. Opin. Struct. Biol., 31, 64–74.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hospital, A., Coni, J. R., Orzco, M., and Gelp, J. L. (2015) Molecular dynamics simulations: advances and applications, Adv. Appl. Bioinform. Chem., 8, 37–47.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Carter, A. P., Clemons, W. M. J., Brodersen, D. E., Morgan-Warren, R., Wimberly, B. T., and Ramakrishnan, V. (2000) Functional insights from the structure of the 30S ribosomal subunit and its interaction with antibiotics, Nature, 407, 340–348.CrossRefPubMedGoogle Scholar
  10. 10.
    Zeng, X., Chugh, J., Casiano-Negroni, A., Al-Hashimi, H. M., and Brooks, C. L., 3rd. (2014) Flipping of the ribosomal A-site adenines provides a basis for tRNA selection, J. Mol. Biol., 426, 3201–3213.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Knight, J. L., and Brooks, C. L. (2009) λ-Dynamics free energy simulation methods, J. Comput. Chem., 30, 1692–1700.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Satpati, P., Bauer, P., and Aqvist, J. (2014) Energetic tuning by tRNA modifications ensures correct decoding of isoleucine and methionine on the ribosome, Chemistry, 20, 10271–10275.CrossRefPubMedGoogle Scholar
  13. 13.
    Satpati, P., and Aqvist, J. (2014) Why base tautomerization does not cause errors in mRNA decoding on the ribosome, Nucleic Acids Res., 42, 12876–12884.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Chirkova, A., Erlacher, M., Clementi, N., Zywicki, M., Aigner, M., and Polacek, N. (2010) The role of the universally conserved A2450-C2063 base pair in the ribosomal peptidyl transferase center, Nucleic Acids Res., 38, 4844–4855.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Englander, M. T., Avins, J. L., Fleisher, R. C., Liu, B., Effraim, P. R., Wang, J., Schulten, K., Leyh, T. S., Gonzalez, R. L., and Cornish, V. W. (2015) The ribosome can discriminate the chirality of amino acids within its peptidyl-transferase center, Proc. Natl. Acad. Sci. USA, 112, 6038–6043.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Brandman, R., Brandman, Y., and Pande, V. S. (2012) Asite residues move independently from P-site residues in all-atom molecular dynamics simulations of the 70S bacterial ribosome, PLoS One, 7, e29377.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Whitford, P. C., Ahmed, A., Yu, Y., Hennely, S. P., Tama, F., Spahn, C. M., Onuchic, J. N., and Sanbonmatsu, K. Y. (2011) Excited states of ribosome translocation revealed through integrative molecular modeling, Proc. Natl. Acad. Sci. USA, 108, 18943–8948.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Whitford, P. C., and Sanbonmatsu, K. Y. (2013) Simulating movement of tRNA through the ribosome during hybridstate formation, J. Chem. Phys., 139, 121919.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Noel, J. K., Whitford, P. C., Sanbonmatsu, K. Y., and Onuchic, J. N. (2010) SMOG@ctbp: simplified deployment of structure-based models in GROMACS, Nucleic Acids Res., 38, W657–W661.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Whitford, P. C., Blanchard, S. C., Cate, J. H. D., and Sanbonmatsu, K. Y. (2013) Connecting the kinetics and energy landscape of tRNA translocation on the ribosome, PLoS Comput. Biol., 9, e1003003.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bock, L. V., Blau, C., Schroder, G. F., Davydov, I. I., Fischer, N., Stark, H., Rodnina, V., Vaiana, A. C., and Grubmuller, H. (2013) Energy barriers and driving forces in tRNA translocation through the ribosome, Nat. Struct. Mol. Biol., 20, 1390–1396.CrossRefPubMedGoogle Scholar
  22. 22.
    Ishida, H., and Matsumoto, A. (2014) Free-energy landscape of reverse tRNA: translocation through the ribosome analyzed by electron microscopy density maps and molecular dynamics simulations, PLoS One, 9, e101951.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Bock, L. V., Blau, C., Vaiana, A. C., and Grubmuller, H. (2015) Dynamic contact network between ribosomal subunits enables rapid large-scale rotation during spontaneous translocation, Nucleic Acids Res., 43, 6747–6760.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lucent, D., Snow, C., Aitken, C., and Pande, V. (2010) Non-bulk-like solvent behavior in the ribosome exit tunnel, PLoS Comput. Biol., 6, e1000963.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Petrone, P., Snow, C., Lucent, D., and Pande, V. (2008) Side-chain recognition and gating in the ribosome exit tunnel, Proc. Natl. Acad. Sci. USA, 105, 16549–16554.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Ishida, H., and Hayward, S. (2008) Path of nascent polypeptide in exit tunnel revealed by molecular dynamics simulation of ribosome, Biophys. J., 95, 5962–5973.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Nilsson, O. B., Hedman, R., Marino, J., Wickles, S., Bischoff, L., Johansson, M., Muller-Lucks, A., Trovato, F., Puglisi, J. D., O’Brien, E. P., Beckmann, R., and Von Heijne, G. (2015) Cotranslational protein folding inside the ribosome exit tunnel, Cell Rep., 12, 1533–1540.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Makarov, G. I., Golovin, A. V., Sumbatyan, N. V., and Bogdanov, A. A. (2015) Molecular dynamics investigation of a mechanism of allosteric signal transmission in ribosomes, Biochemistry (Moscow), 80, 1047–1056.CrossRefGoogle Scholar
  29. 29.
    Vazquez-Laslop, N., Ramu, H., Klepacki, D., Kannan, K., and Mankin, A. S. (2010) The key function of a conserved and modified rRNA residue in the ribosomal response to the nascent peptide, EMBO J., 29, 3108–3117.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Alexandrov, A., and Simonson, T. (2008) Molecular dynamics simulations of the 30S ribosomal subunit reveal a preferred tetracycline binding site, J. Amer. Chem. Soc., 130, 1114–1115.CrossRefGoogle Scholar
  31. 31.
    Vaiana, A., and Sanbonmatsu, K. (2009) Stochastic gating and drug–ribosome interactions, J. Mol. Biol., 386, 648–661.CrossRefPubMedGoogle Scholar
  32. 32.
    Romanowska, J., McCammon, J., and Trylska, J. (2011) Understanding the origins of bacterial resistance to aminoglycosides through molecular dynamics mutational study of the ribosomal A-site, PLoS Comput. Biol., 7, e1002099.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Panecka, J., Mura, C., and Trylska, J. (2014) Interplay of the bacterial ribosomal A-site, s12 protein mutations and paromomycin binding: a molecular dynamics study, PLoS One, 9, e111811.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wolf, A., Baumann, S., Arndt, H. D., and Kirschner, K. N. (2012) Influence of thiostrepton binding on the ribosomal GTPase associated region characterized by molecular dynamics simulation, Bioorg. Med. Chem., 20, 7194–7205.CrossRefPubMedGoogle Scholar
  35. 35.
    Ge, X., and Roux, B. (2010) Calculation of the standard binding free energy of sparsomycin to the ribosomal peptidyl-transferase P-site using molecular dynamics simulations with restraining potentials, J. Mol. Recogn., 23, 128–141.CrossRefGoogle Scholar
  36. 36.
    Yam, W. K., and Wahab, H. A. (2009) Molecular insights into 14-membered macrolides using the MM-PBSA method, J. Chem. Inf. Model., 49, 1558–1567.CrossRefPubMedGoogle Scholar
  37. 37.
    Saini, J., Homeyer, N., Fulle, S., and Gohlke, H. (2013) Determinants of the species selectivity of oxazolidinone antibiotics targeting the large ribosomal subunit, Biol. Chem., 394, 1529–1541.CrossRefPubMedGoogle Scholar
  38. 38.
    Sothiselvam, S., Liu, B., Han, W., Ramu, H., Klepacki, D., Atkinson, G. C., Brauer, A., Remm, M., Tenson, T., Schulten, K., Vazquez-Laslop, N., and Mankin, A. S. (2014) Macrolide antibiotics allosterically predispose the ribosome for translation arrest, Proc. Natl. Acad. Sci. USA, 111, 9804–9809.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Gupta, P., Liu, B., Klepacki, D., Gupta, V., Schulten, K., Mankin, A. S., and Vazquez-Laslop, N. (2016) Nascent peptide assists the ribosome in recognizing chemically distinct small molecules, Nat. Chem. Biol., 12, 153–158.CrossRefPubMedGoogle Scholar
  40. 40.
    Arenz, S., Bock, L. V., Graf, M., Innis, C. A., Beckmann, R., Grubmüller, H., Vaiana, A. C., and Wilson, D. N. (2016) A combined cryo-EM and molecular dynamics approach reveals the mechanism of ErmBL-mediated translation arrest, Nat. Commun., 7, 12026.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Small, M. C., Lopes, P., Andrade, R. B., and MacKerell, A. D., Jr. (2013) Impact of ribosomal modification on the binding of the antibiotic telithromycin using a combined grand canonical Monte Carlo/molecular dynamics simulation approach, PLoS Comput. Biol., 9, e1003113.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Wang, Y., Shen, J. K., and Schroeder, S. J. (2012) Nucleotide dynamics at the A-site cleft in the peptidyltransferase center of H. marismortui 50S ribosomal subunits, J. Phys. Chem. Lett., 8, 1007–1010.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2016

Authors and Affiliations

  • G. I. Makarov
    • 1
    • 2
  • T. M. Makarova
    • 1
    • 2
  • N. V. Sumbatyan
    • 1
    • 2
  • A. A. Bogdanov
    • 1
    • 2
    Email author
  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  2. 2.Lomonosov Moscow State University, Chemistry DepartmentMoscowRussia

Personalised recommendations