Advertisement

QM/MM MD and Free Energy Simulation Study of Methyl Transfer Processes Catalyzed by PKMTs and PRMTs

  • Yuzhuo ChuEmail author
  • Hong Guo
Original Research Article

Abstract

Methyl transfer processes catalyzed by protein lysine methyltransferases (PKMTs) and protein arginine methyltransferases (PRMTs) control important biological events including transcriptional regulation and cell signaling. One important property of these enzymes is that different PKMTs and PRMTs catalyze the formation of different methylated product (product specificity). These different methylation states lead to different biological outcomes. Here, we review the results of quantum mechanics/molecular mechanics molecular dynamics and free energy simulations that have been performed to study the reaction mechanism of PKMTs and PRMTs and the mechanism underlying the product specificity of the methyl transfer processes.

Keywords

Methyl transfer PKMT PRMT Product specificity QM/MM MD Free energy simulations Reaction mechanism 

References

  1. 1.
    Jenuwein T (2006) The epigenetic magic of histone lysine methylation. Febs J 273(14):3121–3135. doi: 10.1111/j.1742-4658.2006.05343.x CrossRefGoogle Scholar
  2. 2.
    Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6(11):838–849. doi: 10.1038/nrm1761 CrossRefGoogle Scholar
  3. 3.
    Trievel RC (2004) Structure and function of histone methyltransferases. Crit Rev Eukaryot Gene Expr 14(3):147–169CrossRefGoogle Scholar
  4. 4.
    Dillon SC, Zhang X, Trievel RC, Cheng X (2005) The SET-domain protein superfamily: protein lysine methyltransferases. Genome Biol 6(8):227. doi: 10.1186/gb-2005-6-8-227 CrossRefGoogle Scholar
  5. 5.
    Cheng X, Collins RE, Zhang X (2005) Structural and sequence motifs of protein (histone) methylation enzymes. Annu Rev Biophys Biomol Struct 34:267–294. doi: 10.1146/annurev.biophys.34.040204.144452 CrossRefGoogle Scholar
  6. 6.
    Xiao B, Jing C, Wilson JR, Walker PA, Vasisht N, Kelly G, Howell S, Taylor IA, Blackburn GM, Gamblin SJ (2003) Structure and catalytic mechanism of the human histone methyltransferase SET7/9. Nature 421(6923):652–656. http://www.nature.com/nature/journal/v421/n6923/suppinfo/nature01378_S1.html CrossRefGoogle Scholar
  7. 7.
    Xiao B, Wilson JR, Gamblin SJ (2003) SET domains and histone methylation. Curr Opin Struct Biol 13(6):699–705CrossRefGoogle Scholar
  8. 8.
    Li B, Carey M, Workman JL (2007) The role of chromatin during transcription. Cell 128(4):707–719. doi: 10.1016/j.cell.2007.01.015 CrossRefGoogle Scholar
  9. 9.
    Taverna SD, Li H, Ruthenburg AJ, Allis CD, Patel DJ (2007) How chromatin-binding modules interpret histone modifications: lessons from professional pocket pickers. Nat Struct Mol Biol 14(11):1025–1040. doi: 10.1038/nsmb1338 CrossRefGoogle Scholar
  10. 10.
    Collins RE, Tachibana M, Tamaru H, Smith KM, Jia D, Zhang X, Selker EU, Shinkai Y, Cheng X (2005) In vitro and in vivo analyses of a Phe/Tyr switch controlling product specificity of histone lysine methyltransferases. J Biol Chem 280(7):5563–5570. doi: 10.1074/jbc.M410483200 CrossRefGoogle Scholar
  11. 11.
    Zhang X, Yang Z, Khan SI, Horton JR, Tamaru H, Selker EU, Cheng X (2003) Structural basis for the product specificity of histone lysine methyltransferases. Mol Cell 12(1):177–185CrossRefGoogle Scholar
  12. 12.
    Del Rizzo PA, Couture JF, Dirk LM, Strunk BS, Roiko MS, Brunzelle JS, Houtz RL, Trievel RC (2010) SET7/9 catalytic mutants reveal the role of active site water molecules in lysine multiple methylation. J Biol Chem 285(41):31849–31858. doi: 10.1074/jbc.M110.114587 CrossRefGoogle Scholar
  13. 13.
    Wu H, Min J, Lunin VV, Antoshenko T, Dombrovski L, Zeng H, Allali-Hassani A, Campagna-Slater V, Vedadi M, Arrowsmith CH, Plotnikov AN, Schapira M (2010) Structural biology of human H3K9 methyltransferases. PLoS One 5(1):e8570. doi: 10.1371/journal.pone.0008570 CrossRefGoogle Scholar
  14. 14.
    Bedford MT, Clarke SG (2009) Protein arginine methylation in mammals: who, what, and why. Mol Cell 33(1):1–13. doi: 10.1016/j.molcel.2008.12.013 CrossRefGoogle Scholar
  15. 15.
    Lee HW, Kim S, Paik WK (1977) S-adenosylmethionine: protein-arginine methyltransferase. Purification and mechanism of the enzyme. Biochemistry 16(1):78–85CrossRefGoogle Scholar
  16. 16.
    Di Lorenzo A, Bedford MT (2011) Histone arginine methylation. FEBS Lett 585(13):2024–2031. doi: 10.1016/j.febslet.2010.11.010 CrossRefGoogle Scholar
  17. 17.
    Wysocka J, Allis CD, Coonrod S (2006) Histone arginine methylation and its dynamic regulation. Front Biosci 11:344–355CrossRefGoogle Scholar
  18. 18.
    Lin H, Truhlar DG (2007) QM/MM: What have we learned, where are we, and where do we go from here? Theor Chem Acc 117(2):185–199. doi: 10.1007/s00214-006-0143-z CrossRefGoogle Scholar
  19. 19.
    Guo H, Salahub DR (2001) Origin of the high basicity of 2,7-dimethoxy-1,8-bis-(dimethylamino)naphthalene: Implications for enzyme catalysis. J Mol Struct Theochem 547:113–118. doi: 10.1016/s0166-1280(01)00463-8 CrossRefGoogle Scholar
  20. 20.
    Guo H, Paldus J (1997) Estimates of the structure and dimerization energy of polyacetylene from ab initio calculations on finite polyenes. Int J Quantum Chem 63(2):345–360. doi: 10.1002/(sici)1097-461x(1997)63:2<345::aid-qua6>3.0.co;2-w CrossRefGoogle Scholar
  21. 21.
    Guo HB, Beahm RF, Guo H (2004) Stabilization and destabilization of the C-delta-h center dot center dot center dot O=C hydrogen bonds involving proline residues in helices. J Phys Chem B 108(46):18065–18072. doi: 10.1021/jp0480192 CrossRefGoogle Scholar
  22. 22.
    Warshel A, Levitt M (1976) Theoretical studies of enzymic reactions: dielectric, electrostatic and steric stabilization of the carbonium ion in the reaction of lysozyme. J Mol Biol 103(2):227–249CrossRefGoogle Scholar
  23. 23.
    Guo H, Wlodawer A, Nakayama T, Xu Q, Guo H (2006) Catalytic role of proton transfers in the formation of a tetrahedral adduct in a serine carboxyl peptidase. Biochemistry 45(30):9129–9137. doi: 10.1021/bi060461i CrossRefGoogle Scholar
  24. 24.
    Guo HB, Rao N, Xu Q, Guo H (2005) Origin of tight binding of a near-perfect transition-state analogue by cytidine deaminase: Implications for enzyme catalysis. J Am Chem Soc 127(9):3191–3197. doi: 10.1021/ja0439625 CrossRefGoogle Scholar
  25. 25.
    Hu P, Wang S, Zhang Y (2008) COMP 169-How do SET-domain protein lysine methyltransferases achieve the methylation state specificity? An ab initio QM/MM molecular dynamics study, Abstr Pap Am Chem S 235Google Scholar
  26. 26.
    Hu P, Wang S, Zhang Y (2008) How do SET-domain protein lysine methyltransferases achieve the methylation state specificity? Revisited by ab initio QM/MM molecular dynamics simulations. J Am Chem Soc 130(12):3806–3813. doi: 10.1021/ja075896n CrossRefGoogle Scholar
  27. 27.
    Wang SL, Hu P, Zhang YK (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis: The case of histone lysine methyltransferase SET7/9. J Phys Chem B 111(14):3758–3764. doi: 10.1021/jp067147i CrossRefGoogle Scholar
  28. 28.
    Xu Q, Guo H-B, Wlodawer A, Nakayama T, Guo H (2007) The QM/MM molecular dynamics and free energy simulations of the acylation reaction catalyzed by the serine-carboxyl peptidase kumamolisin-As. Biochemistry 46(12):3784–3792. doi: 10.1021/bi061737p CrossRefGoogle Scholar
  29. 29.
    Xu Q, Guo H, Gorin A, Guo H (2007) Stabilization of a transition-state analogue at the active site of yeast cytosine deaminase: Importance of proton transfers. J Phys Chem B 111(23):6501–6506. doi: 10.1021/jp0670743 CrossRefGoogle Scholar
  30. 30.
    Xu Q, Guo H, Wlodawer A, Guo H (2006) The importance of dynamics in substrate-assisted catalysis and specificity. J Am Chem Soc 128(18):5994–5995. doi: 10.1021/ja058831y CrossRefGoogle Scholar
  31. 31.
    Xu Q, Li L, Guo H (2010) Understanding the mechanism of deacylation reaction catalyzed by the serine carboxyl peptidase kumamolisin-as: insights from QM/MM free energy simulations. J Phys Chem B 114(32):10594–10600. doi: 10.1021/jp102785s CrossRefGoogle Scholar
  32. 32.
    Yao J, Xu Q, Chen F, Guo H (2011) QM/MM free energy simulations of salicylic acid methyltransferase: effects of stabilization of TS-like structures on substrate specificity. J Phys Chem B 115(2):389–396. doi: 10.1021/jp1086812 CrossRefGoogle Scholar
  33. 33.
    Zhang X, Bruice TC (2008) Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases. Proc Natl Acad Sci USA 105(15):5728–5732. doi: 10.1073/pnas.0801788105 CrossRefGoogle Scholar
  34. 34.
    Chu Y, Li G, Guo H (2013) QM/MM MD and free energy simulations of the methylation reactions catalyzed by protein arginine methyltransferase PRMT3. Can J Chem 91(7):605–612. doi: 10.1139/cjc-2012-0483 CrossRefGoogle Scholar
  35. 35.
    Guo H-B, Guo H (2007) Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity. Proc Natl Acad Sci USA 104(21):8797–8802. doi: 10.1073/pnas.0702981104 CrossRefGoogle Scholar
  36. 36.
    Xu Q, Chu YZ, Guo HB, Smith JC, Guo H (2009) Energy triplets for writing epigenetic marks: insights from QM/MM free-energy simulations of protein lysine methyltransferases. Chem Eur J 15(46):12596–12599. doi: 10.1002/chem.200902297 CrossRefGoogle Scholar
  37. 37.
    Chu Y, Xu Q, Guo H (2010) Understanding energetic origins of product specificity of SET8 from QM/MM Free Energy Simulations: What causes the stop of methyl addition during histone lysine methylation? J Chem Theor Comput 6(4):1380–1389. doi: 10.1021/ct9006458 CrossRefGoogle Scholar
  38. 38.
    Chu Y, Yao J, Guo H (2012) QM/MM MD and free energy simulations of G9a-like protein (GLP) and its mutants: understanding the factors that determine the product specificity. Plos One 7(5). doi: 10.1371/journal.pone.0037674 CrossRefGoogle Scholar
  39. 39.
    Chuikov S, Kurash JK, Wilson JR, Xiao B, Justin N, Ivanov GS, McKinney K, Tempst P, Prives C, Gamblin SJ, Barlev NA, Reinberg D (2004) Regulation of p53 activity through lysine methylation. Nature 432(7015):353–360. doi: 10.1038/nature03117 CrossRefGoogle Scholar
  40. 40.
    Yao J, Chu Y, An R, Guo H (2012) Understanding product specificity of protein lysine methyltransferases from QM/MM molecular dynamics and free energy simulations: the effects of mutation on SET7/9 beyond the Tyr/Phe switch. J Chem Inf Model 52(2):449–456. doi: 10.1021/ci200364m CrossRefGoogle Scholar
  41. 41.
    Tamaru H, Zhang X, McMillen D, Singh PB, Nakayama J, Grewal SI, Allis CD, Cheng XD, Selker EU (2003) Trimethylated lysine 9 of histone H3 is a mark for DNA methylation in Neurospora crassa. Nat Genet 34(1):75–79. doi: 10.1038/ng1143 CrossRefGoogle Scholar
  42. 42.
    Couture JF, Collazo E, Brunzelle JS, Trievel RC (2005) Structural and functional analysis of SET8, a histone H4 Lys-20 methyltransferase. Gene Dev 19(12):1455–1465. doi: 10.1101/gad.1318405 CrossRefGoogle Scholar
  43. 43.
    Nishioka K, Rice JC, Sarma K, Erdjument-Bromage H, Werner J, Wang YM, Chuikov S, Valenzuela P, Tempst P, Steward R, Lis JT, Allis CD, Reinberg D (2002) PR-Set7 is a nucleosome-specific methyltransferase that modifies lysine 20 of histone H4 and is associated with silent chromatin. Mol Cell 9(6):1201–1213. doi: 10.1016/s1097-2765(02)00548-8 CrossRefGoogle Scholar
  44. 44.
    Karachentsev D, Sarma K, Reinberg D, Steward R (2005) PR-Set7-dependent methylation of histone H4 Lys 20 functions in repression of gene expression and is essential for mitosis. Gene Dev 19(4):431–435. doi: 10.1101/gad.1263005 CrossRefGoogle Scholar
  45. 45.
    Couture JF, Dirk LMA, Brunzelle JS, Houtz RL, Trievel RC (2008) Structural origins for the product specificity of SET domain protein methyltransferases. P Natl Acad Sci USA 105(52):20659–20664. doi: 10.1073/pnas.0806712105 CrossRefGoogle Scholar
  46. 46.
    Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H, Shinkai Y (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Gene Dev 16(14):1779–1791. doi: 10.1101/gad989402 CrossRefGoogle Scholar
  47. 47.
    Tachibana M, Ueda J, Fukuda M, Takeda N, Ohta T, Iwanari H, Sakihama T, Kodama T, Hamakubo T, Shinkai Y (2005) Histone methyltransferases G9a and GLP form heteromeric complexes and are both crucial for methylation of euchromatin at H3–K9. Gene Dev 19(7):815–826. doi: 10.1101/gad.1284005 CrossRefGoogle Scholar
  48. 48.
    Zhang X, Cheng X (2003) Structure of the predominant protein arginine methyltransferase PRMT1 and analysis of its binding to substrate peptides. Structure 11(5):509–520CrossRefGoogle Scholar
  49. 49.
    Zhang X, Zhou L, Cheng X (2000) Crystal structure of the conserved core of protein arginine methyltransferase PRMT3. EMBO J 19(14):3509–3519. doi: 10.1093/emboj/19.14.3509 CrossRefGoogle Scholar
  50. 50.
    Rust HL, Zurita-Lopez CI, Clarke S, Thompson PR (2011) Mechanistic studies on transcriptional coactivator protein arginine methyltransferase 1. Biochemistry 50(16):3332–3345. doi: 10.1021/bi102022e CrossRefGoogle Scholar

Copyright information

© International Association of Scientists in the Interdisciplinary Areas and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.School of Life Science and BiotechnologyDalian University of TechnologyDalianChina
  2. 2.Department of Biochemistry and Cellular and Molecular BiologyUniversity of TennesseeKnoxvilleUSA
  3. 3.UT/ORNL Center for Molecular BiophysicsOak Ridge National LaboratoryOak RidgeUSA

Personalised recommendations