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Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine

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Abstract

Each amino acid has its intrinsic propensity for certain local backbone conformations, which can be further modulated by the physicochemical environment and post-translational modifications. In this work, we study the effects of phosphorylation on the intrinsic propensity for different local backbone conformations of serine/threonine by molecular dynamics simulations. We showed that phosphorylation has very different effects on the intrinsic propensity for certain local backbone conformations for the serine and threonine. The phosphorylation of serine increases the propensity of forming polyproline II, whereas that of threonine has the opposite effect. Detailed analysis showed that such different responses to phosphorylation mainly arise from their different perturbations to the backbone hydration and the geometrical constraints by forming side-chain–backbone hydrogen bonds due to phosphorylation. Such an effect of phosphorylation on backbone conformations can be crucial for understanding the molecular mechanism of phosphorylation-regulated protein structures/dynamics and functions.

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References

  1. Walsh, C.T.: Posttranslational Modification of Proteins: Expanding Nature’s Inventory. Colorado: Roberts and Company Publishers, Englewood (2006)

    Google Scholar 

  2. Marks, F.: Protein Phosphorylation. VCH Verlagsgesellschaft mbH, Weinheim, Germany (1996)

    Book  Google Scholar 

  3. Chen, H.F.: Molecular dynamics simulation of phosphorylated KID post-translational modification. PLoS ONE 4, e6516 (2009)

    Article  ADS  Google Scholar 

  4. Jho, Y.S., Zhulina, E.B., Kim, M.W., Pincus, P.A.: Monte Carlo simulations of tau proteins: effect of phosphorylation. Biophys. J 99, 2387–2397 (2010)

    Article  Google Scholar 

  5. Valiev, M., Yang, J., Adams, J.A., Taylor, S.S., Weare, J.H.: Phosphorylation reaction in cAPK protein kinase-free energy quantum mechanical/molecular mechanics simulations. J. Phys. Chem. B 111, 13455–13464 (2007)

    Article  Google Scholar 

  6. Mortishire-Smith, R.J., Pitzenberger, S.M., Burke, C.J., Middaugh, C.R., Garsky, V.M., Johnson, R.G.: Solution structure of the cytoplasmic domain of phospholamban: phosphorylation leads to a local perturbation in secondary structure. Biochemistry 34, 7603–7613 (1995)

    Article  Google Scholar 

  7. Quirk, P.G., Patchell, V.B., Colyer, J., Drago, G.A., Gao, Y.: Conformational effects of serine phosphorylation in phospholamban peptides. Eur. J. Biochem. 236, 85–91 (1996)

    Article  Google Scholar 

  8. Schon, O., Friedler, A., Bycroft, M., Freund, S.M.V., Fersht, A.R.: Molecular mechanism of the interaction between MDM2 and p53. J. Mol. Biol. 323, 491–501 (2002)

    Article  Google Scholar 

  9. Lee, H.J., Srinivasan, D., Coomber, D., Lane, D.P., Verma, C.S.: Modulation of the p53-MDM2 interaction by phosphorylation of Thr18: a computational study. Cell Cycle 6, 2604–2611 (2007)

    Article  Google Scholar 

  10. Fraser, J.A., Vojtesek, B., Hupp, T.R.: A novel p53 phosphorylation site within the MDM2 ubiquitination signal I. Phosphorylation at ser269 in vivo is linked to inactivation of p53 function. J. Biol. Chem. 285, 37762–37772 (2010)

    Article  Google Scholar 

  11. Li, W.F., Wolynes, P.G., Takada, S.: Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins. Proc. Natl. Acad. Sci. U.S.A. 108, 3504–3509 (2011)

    Article  ADS  Google Scholar 

  12. Li, W.F., Wang, W., Takada, S.: Energy landscape views for interplays among folding, binding, and allostery of calmodulin domains. Proc. Natl. Acad. Sci. U.S.A. 111, 10550–10555 (2014)

    Article  ADS  Google Scholar 

  13. Terakawa, T., Takada, S.: Multiscale ensemble modeling of intrinsically disordered proteins: p53 N-terminal domain. Biophys. J. 101, 1450–1458 (2011)

    Article  ADS  Google Scholar 

  14. Li, W.F., Zhang, Z., Wang, J., Wang, W.: Metal-coupled folding of Cys2His2 zinc-finger. J. Am. Chem. Soc. 130, 892–900 (2008)

    Article  Google Scholar 

  15. Mao, X.B., Guo, Y.Y., Luo, Y., Niu, L., Liu, L., Ma, X.J., Wang, H.B., Yang, Y.L., Wei, G.H., Wang, C.: Sequence effects on peptide assembly characteristics observed by using scanning tunneling microscopy. J. Am. Chem. Soc. 135, 2181–2187 (2013)

    Article  Google Scholar 

  16. Li, W.F., Zhang, J., Su, Y., Wang, J., Qin, M., Wang, W.: Effects of zinc binding on the conformational distribution of the amyloid-beta peptide based on molecular dynamics simulations. J. Phys. Chem. B 111, 13814–13821 (2007)

    Article  Google Scholar 

  17. Wang, Y., Chu, X.K., Longhi, S., Roche, P., Han, W., Wang, E.K., Wang, J.: Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein. Proc. Natl. Acad. Sci. U.S.A. 110, E3743–E3752 (2013)

    Article  ADS  Google Scholar 

  18. Jiang, F., Han, W., Wu, Y.D.: The intrinsic conformational features of amino acids from a protein coil library and their applications in force field development. Phys. Chem. Chem. Phys. 15, 3413–3428 (2013)

    Article  Google Scholar 

  19. Jiang, F., Wu, Y.D.: Folding of fourteen small proteins with a residue-specific force field and replica-exchange molecular dynamics. J. Am. Chem. Soc. 136, 9536–9539 (2014)

    Article  Google Scholar 

  20. Kim, S.Y., Jung, Y., Hwang, G.S., Han, H., Cho, M.: Phosphorylation alters backbone conformational preferences of serine and threonine peptides. Proteins 79, 3155–3165 (2011)

    Article  Google Scholar 

  21. Shen, T.Y., Wong, C.F., McCammon, J.A.: Atomistic Brownian dynamics simulation of peptide phosphorylation. J. Am. Chem. Soc. 123, 9107–9111 (2001)

    Article  Google Scholar 

  22. Xiang, S.Q., Gapsys, V., Kim, H.Y., Bessonov, S., Hsiao, H.H., Mohlmann, S., Klaukien, V., Ficner, R., Becker, S., Urlaub, H., Luhrmann, R, De Groot, B., Zweckstetter, M.: Phosphorylation drives a dynamic switch in serine/arginine-rich proteins. Structure 21, 2162–2174 (2003)

    Article  Google Scholar 

  23. Sellis, D., Drosou, V., Vlachakis, D., Voukkalis, N., Giannakouros, T., Vlassi, M.: Phosphorylation of the arginine/serine repeats of lamin B receptor by SRPK1–Insights from molecular dynamics simulations. Biochim. Biophys. Acta 1820, 44–55 (2012)

    Article  Google Scholar 

  24. Vassall, K.A., Bessonov, K., De Avila, M., Polverini, E., Harauz, G.: The effects of threonine phosphorylation on the stability and dynamics of the central molecular switch region of 18.5-kDa myelin basic protein. PLoS ONE 8, e68175 (2013)

    Article  ADS  Google Scholar 

  25. Velazquez, H.A., Hamelberg, D.: Dynamical role of phosphorylation on serine/threonine-proline Pin1 substrates from constant force molecular dynamics simulations. J. Chem. Phys. 142, 075102 (2015)

    Article  ADS  Google Scholar 

  26. Krimm, S., Tiffany, M.L.: Circular-dichroism spectrum and structure of unordered polypeptides and proteins. Isr. J. Chem. 12, 189–200 (1974)

    Article  Google Scholar 

  27. Shi, Z.S., Olson, C.A., Rose, G.D., Baldwin, R.L., Kallenbach, N.R.: Polyproline II structure in a sequence of seven alanine residues. Proc. Natl. Acad. Sci. U.S.A. 99, 9190–9195 (2002)

    Article  ADS  Google Scholar 

  28. Kentsis, A., Mezei, M., Osman, R.: Origin of the sequence-dependent polyproline II structure in unfolded peptides. Proteins 61, 769–776 (2005)

    Article  Google Scholar 

  29. Li, W.F., Qin, M., Tie, Z.X., Wang, W.: Effects of solvents on the intrinsic propensity of peptide backbone conformations. Phys. Rev. E 84, 041933 (2011)

    Article  ADS  Google Scholar 

  30. Liu, Z.G., Chen, K., Ng, A., Shi, Z.S., Woody, R.W., Kallenbach, N.R.: Solvent dependence of PII conformation in model alanine peptides. J. Am. Chem. Soc. 126, 15141–15150 (2004)

    Article  Google Scholar 

  31. Lindorff-Larsen, K., Piana, S., Palmo, K., Maragakis, P., Klepeis, J.L., Dror, R.O., Shaw, D.E.: Improved side-chain torsion potentials for Amber99SB protein force field. Proteins 78, 1950–1958 (2010)

    Google Scholar 

  32. Jiang, F., Zhou, C.Y., Wu, Y.D.: Residue-specific force field based on the protein coil library. RSFF1: modification of OPLS-AA/L. J. Phys. Chem. B 118, 6983–6998 (2014)

    Article  Google Scholar 

  33. Hagarman, A., Measey, T.J., Mathieu, D., Schwalbe, H., Schweitzer-Stenner, R.: Intrinsic propensities of amino acid residues in GxG peptides inferred from amide I’ band profiles and NMR scalar coupling constants. J. Am. Chem. Soc. 132, 540–551 (2010)

    Article  Google Scholar 

  34. Shi, Z.S., Chen, K., Liu, Z.G., Ng, A., Bracken, W.C., Kallenbach, N.R.: Polyproline II propensities from GGXGG peptides reveal an anticorrelation with beta-sheet scales. Proc. Natl. Acad. Sci. U.S.A. 102, 17964–17968 (2005)

    Article  ADS  Google Scholar 

  35. Plaxco, K.W., Morton, C.J., Grimshaw, S.B., Jones, J.A., Pitkeathly, M., Campbell, I.D., Dobson, C.M.: The effects of guanidine hydrochloride on the ‘random coil’ conformations and NMR chemical shifts of the peptide series GGXGG. J. Biomol. NMR 10, 221–230 (1997)

    Article  Google Scholar 

  36. van der Spoel, D.: The solution conformations of amino acids from molecular dynamics simulations of Gly-X-Gly peptides: comparison with NMR parameters. Biochem. Cell Biol. 76, 164–170 (1998)

    Article  Google Scholar 

  37. He, L., Navarro, A.E., Shi, Z.S., Kallenbach, N.R.: End effects influence short model peptide conformation. J. Am. Chem. Soc. 134, 1571–1576 (2012)

    Article  Google Scholar 

  38. Toal, S., Meral, D., Verbaro, D., Urbanc, B., Schweitzer-Stenner, R.: pH-independence of trialanine and effects of termini blocking in short peptides: a combined vibrational, NMR, UVCD and molecular dynamics study. J. Phys. Chem. B 117, 3689–3706 (2013)

    Article  Google Scholar 

  39. Dean, A.M., Koshland, D.E.: Electrostatic and steric contributions to regulation at the active site of isocitrate dehydrogenase. Science 249, 1044–1046 (1990)

    Article  ADS  Google Scholar 

  40. Case, D A, Darden, T.A., Cheatham, III, T.E., Simmerling, C.L., Wang, J., Duke, R.E., Luo, R., Walker, R.C., Zhang, W., Merz, K.M., Roberts, B., Wang, B., Hayik, S., Roitberg, A., Seabra, G., Kolossvry, I., Wong, K.F., Paesani, F., Vanicek, J., Liu, J., Wu, X., Brozell, S.R., Steinbrecher, T., Gohlke, H., Cai, Q., Ye, X., Wang, J., Hsieh, M.-J., Cui, G., Roe, D.R., Mathews, D.H., Seetin, M.G., Sagui, C., Babin, V., Luchko, T., Gusarov, S., Kovalenko, A., Kollman, P.A.: AMBER 11. University of California, San Francisco (2010)

  41. Duan, Y., Wu, C., Chowdhury, S., Lee, M.C., Xiong, G.M., Zhang, W., Yang, R., Cieplak, P., Luo, R., Lee, T., Caldwell, J., Wang, J.M., Kollman, P.: A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations. J. Comput. Chem. 24, 1999–2012 (2003)

    Article  Google Scholar 

  42. Craft, J.W., Legge, G.B.: An AMBER/DYANA/MOLMOL phosphorylated amino acid library set and incorporation into NMR structure calculations. J. Biomol. NMR 33, 15–24 (2005)

    Article  Google Scholar 

  43. Best, R.B., Zhu, X., Shim, J., Lopes, P.E.M., Mittal, J., Feig, M., MacKerell, A.D.: Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ(1) and χ(2) dihedral angles. J. Chem. Theory. Comput. 8, 3257–3273 (2012)

    Article  Google Scholar 

  44. MacKerell, A.D., Feig, M., Brooks, C.L.: Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J. Comput. Chem. 25, 1400–1415 (2004)

    Article  Google Scholar 

  45. MacKerell, A.D., Bashford, D., Bellott, M., Dunbrack, R.L., Evanseck, J.D., Field, M.J., Fischer, S., Gao, J., Guo, H., Ha, S.: All-atom empirical potential for molecular modeling and dynamics studies of proteins. J. Phys. Chem. B 102, 3586–3616 (1998)

    Article  Google Scholar 

  46. Berendsen, H. J. C., Van der Spoel, D., Van Drunen, R.: GROMACS: A message-passing parallel molecular dynamics implementation. Comp. Phys. Comm. 91, 43–56 (1995)

    Article  ADS  Google Scholar 

  47. Van der Spoel, D., Lindahl, E., Hess, B., Groenhof, G., Mark, A.E., Berendsen, H.J.C.: GROMACS: Fast, Flexible and Free. J. Comp. Chem. 26, 1701–1718 (2005)

    Article  Google Scholar 

  48. Hess, B., Kutzner, C., van der Spoel, D., Lindahl, E.: GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory. Comput. 4, 435–447 (2008)

    Article  Google Scholar 

  49. Jorgensen, W.L., Chandrasekhar, J., Madura, J.D., Impey, R.W., Klein, M.L.: Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983)

    Article  ADS  Google Scholar 

  50. Van Gunsteren, W.F., Berendsen, H.J.C.: Algorithms for macromolecular dynamics and constraint dynamics. Mol. Phys. 34, 1311–1327 (1977)

    Article  ADS  Google Scholar 

  51. Darden, T., York, D., Pedersen, L.: Particle mesh Ewald: an N ∗log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993)

    Article  ADS  Google Scholar 

  52. Sugita, Y., Okamoto, Y.: Replica-exchange molecular dynamics method for protein folding. Chem. Phys. Lett. 314, 141–151 (1999)

    Article  ADS  Google Scholar 

  53. Walter, N., Hansmann, U.H.E.: Dynamics and optimal number of replicas in parallel tempering simulations. Phys. Rev. E 76, 065701 (2007)

    Article  ADS  Google Scholar 

  54. Garcia, A.E.: Characterization of non-alpha helical conformations in Ala peptides. Polymer 45, 669–676 (2004)

    Article  Google Scholar 

  55. Avbelj, F., Luo, P.Z., Baldwin, R.L.: Energetics of the interaction between water and the helical peptide group and its role in determining helix propensities. Proc. Natl. Acad. Sci. U.S.A. 97, 10786–10791 (2000)

    Article  ADS  Google Scholar 

  56. Avbelj, F., Baldwin, R.L.: Origin of the neighboring residue effect on peptide backbone conformation. Proc. Natl. Acad. Sci. U.S.A. 101, 10967–10972 (2000)

    Article  ADS  Google Scholar 

  57. Poon, C.D., Samulski, E.T., Weise, C.F., Weisshaar, J.C.: Do bridging water molecules dictate the structure of a model dipeptide in aqueous solution. J. Am. Chem. Soc. 122, 5642–5643 (2000)

    Article  Google Scholar 

  58. Creamer, T.P., Campbell, M.N.: Determinants of the polyproline II helix from modeling studies. Adv. Protein Chem. 62, 263–282 (2002)

    Article  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Grant numbers 11574132, 11174133, 11174134, and 11274157) and Jiangsu Province (BK2011546). W.L. also acknowledges the support of the Program for New Century Excellent Talents in University and the PAPD project of Jiangsu higher education institutions. The numerical calculations in this paper have been done on the IBM Blade cluster system in the High Performance Computing Center of Nanjing University.

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Authors and Affiliations

  1. National Laboratory of Solid State Microstructure, Department of Physics, Nanjing University, Nanjing, 210093, People’s Republic of China

    Erbin He, Jian Zhang, Jun Wang & Wenfei Li

  2. Collaborative Innovation Center of Advanced Microstructures, Nanjing University, Nanjing, 210093, People’s Republic of China

    Erbin He, Jian Zhang, Jun Wang & Wenfei Li

  3. Department of Mathematics and Physics, Nanjing Institute of Technology, Nanjing, 211167, People’s Republic of China

    Guanghui Yan

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  1. Erbin He
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Correspondence to Jun Wang or Wenfei Li.

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He, E., Yan, G., Zhang, J. et al. Effects of phosphorylation on the intrinsic propensity of backbone conformations of serine/threonine. J Biol Phys 42, 247–258 (2016). https://doi.org/10.1007/s10867-015-9405-0

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