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Computational Modeling of Biological Systems: The LDH Story

  • Silvia Ferrer
  • Sergio Martí
  • Vicent Moliner
  • Iñaki Tuñón
Chapter
Part of the Challenges and Advances in Computational Chemistry and Physics book series (COCH, volume 12)

Abstract

Lactate dehydrogenases, LDH, catalyzed reaction has been used in this chapter as a conductor wire to present the evolution and difficulties on computing methods to model chemical reactions in enzymes, since the early calculations based at semiempirical level carried out in gas phase to the recent sophisticated simulations based on hybrid Quantum Mechanical/Molecular Mechanics Dynamics (QM/MM MD) schemes. LDH catalyzes the reversible transformation of pyruvate into lactate. The chemical step consists in a hydride and a proton transfer from the cofactor (NADH) and a protonated histidine (His195), respectively. This fact has generated a lot of controversy about the timing of both transfers in the active site, as well as the role of the different aminoacids of the active site and problems related with the flexibility of the protein. We herein show how an adequate method within a realistic model, taking into account the pKa of the titratable aminoacids, the flexibility of the protein, the size of the MM and QM region or the level of theory used to describe the QM region, must be used to obtain reliable conclusions. Finally, and keeping in mind the size of the system under study, it has been demonstrated the need of performing statistical simulations to sample the full conformational space of all states involved in the reaction, that allow getting free energies and averaged properties directly compared with experimental data.

Keywords

Lactate dehydrogenase LDH Enzyme catalysis Molecular mechanisms Molecular modeling of biomolecules Hybrid quantum mechanic/molecular mechanics Hybrid molecular dynamics Potential energy surfaces Transition state characterizations Potential of mean force Statistical simulations 

Notes

Acknowledgements

We thank the Spanish Ministry Ministerio de Ciencia e Inovación for project CTQ2009-14541, Universitat Jaume I - BANCAIXA Foundation for projects P1·1B2005-13, P1·1B2005-15 and P1·1B2005-27, and Generalitat Valenciana for Prometeo/2009/053 project. We are also grateful to Prof. Ian H. Williams and Prof. J. Andrés for fruitful discussions. The authors also acknowledge the Servei d´Informatica, Universitat Jaume I for generous allotment of computer time. V. Moliner would like to thank the Spanish Ministry Ministerio de Ciencia e Innovación for traveling financial support, project PR2009-0539.

References

  1. 1.
    Ertl G, Gloyna T (2003) Zeitschrift Fur Physikalische Chemie-Int J Res Phys Chem Chem Phys 217(10):1207–1219CrossRefGoogle Scholar
  2. 2.
    Ostwald W (1902) Phys Z 3:313–322Google Scholar
  3. 3.
    Ostwald W (1910) Ann Naturphil 9:1Google Scholar
  4. 4.
    Corma A (2004) Cat Rev Sci Eng 46(3–4):369–417CrossRefGoogle Scholar
  5. 5.
    Garcia-Viloca M, Gao J, Karplus M, Truhlar DG (2004) Science 303(5655):186–195CrossRefGoogle Scholar
  6. 6.
    Warshel A, Sharma PK, Kato M, Xiang Y, Liu HB, Olsson MHM (2006) Chem Rev 106(8):3210–3235CrossRefGoogle Scholar
  7. 7.
    Truhlar DG (2008) J Am Chem Soc 130(50):16824–16827CrossRefGoogle Scholar
  8. 8.
    Field MJ (2007) A practical introduction to the simulation of molecular systems. Cambridge University Press, CambridgeCrossRefGoogle Scholar
  9. 9.
    Warshel A, Levitt M (1976) J Mol Biol 103(2):227–249CrossRefGoogle Scholar
  10. 10.
    Kollman P (1993) Chem Rev 93(7):2395–2417CrossRefGoogle Scholar
  11. 11.
    Kollman PA, Kuhn B, Donini O, Perakyla M, Stanton R, Bakowies D (2001) Acc Chem Res 34(1):72–79CrossRefGoogle Scholar
  12. 12.
    Marti S, Andres J, Moliner V, Silla E, Tuñón I, Bertran J, Field MJ (2001) J Am Chem Soc 123(8):1709–1712CrossRefGoogle Scholar
  13. 13.
    Marti S, Roca M, Andres J, Moliner V, Silla E, Tuñón I, Bertran J (2004) Chem Soc Rev 33(2):98–107CrossRefGoogle Scholar
  14. 14.
    Marti S, Andres J, Moliner V, Silla E, Tuñón I, Bertran J (2008) Chem Soc Rev 37(12):2634–2643CrossRefGoogle Scholar
  15. 15.
    Gao JL, Truhlar DG (2002) Annu Rev Phys Chem 53:467–505CrossRefGoogle Scholar
  16. 16.
    Villa J, Warshel A (2001) J Phys Chem B 105(33):7887–7907CrossRefGoogle Scholar
  17. 17.
    Warshel A (1998) J Biol Chem 273(42):27035–27038CrossRefGoogle Scholar
  18. 18.
    Lin H, Truhlar DG (2007) Theor Chem Acc 117(2):185–199CrossRefGoogle Scholar
  19. 19.
    Clarke AR, Wigley DB, Chia WN, Barstow D, Atkinson T, Holbrook JJ (1986) Nature 324(6098):699–702CrossRefGoogle Scholar
  20. 20.
    Hart KW, Clarke AR, Wigley DB, Chia WN, Barstow DA, Atkinson T, Holbrook JJ (1987) Biochem Biophys Res Commun 146(1):346–353CrossRefGoogle Scholar
  21. 21.
    Clarke AR, Atkinson T, Holbrook JJ (1989) Biochem Sci 14:145–148CrossRefGoogle Scholar
  22. 22.
    Badcoe IG, Smith CJ, Wood S, Halsall DJ, Holbrook JJ, Lund P, Clarke AR (1991) Biochemistry 30(38):9195–9200CrossRefGoogle Scholar
  23. 23.
    Deng H, Zheng J, Clarke A, Holbrook JJ, Callender R, Burgner JW (1994) Biochemistry 33(8):2297–2305CrossRefGoogle Scholar
  24. 24.
    Clarke AR, Wigley DB, Barstow DA, Chia WN, Waldman ADB, Hart KW, Atkinson T, Holbrook JJ (1987) Biochem Soc Trans 15(1):152–153Google Scholar
  25. 25.
    Andres J, Moliner V, Krechl J, Silla E (1993) Bioorg Chem 21(3):260–274CrossRefGoogle Scholar
  26. 26.
    Andres J, Moliner V, Safont VS (1994) J Chem Soc Faraday Trans 90(12):1703–1707CrossRefGoogle Scholar
  27. 27.
    Andres J, Moliner V, Krechl J, Silla E (1995) J Chem Soc Perkin Trans 2(7):1551–1558Google Scholar
  28. 28.
    Krechl J, Kuthan J (1988) Theochem J Mol Struct 47:239–244CrossRefGoogle Scholar
  29. 29.
    Wilkie J, Williams IH (1992) J Am Chem Soc 114(13):5423–5425CrossRefGoogle Scholar
  30. 30.
    Wilkie J, Williams IH (1995) J Chem Soc Perkin Trans 2(7):1559–1567Google Scholar
  31. 31.
    Ranganathan S, Gready JE (1994) J Chem Soc Farad Trans 90(14):2047–2056CrossRefGoogle Scholar
  32. 32.
    Yadav A, Jackson RM, Holbrook JJ, Warshel A (1991) J Am Chem Soc 113(13):4800–4805CrossRefGoogle Scholar
  33. 33.
    Siegbahn PEM, Himo F (2009) J Biol Inorg Chem 14(5):643–651CrossRefGoogle Scholar
  34. 34.
    de la Lande A, Gerard H, Moliner V, Izzet G, Reinaud O, Parisel O (2006) J Biol Inorg Chem 11(5):593–608CrossRefGoogle Scholar
  35. 35.
    de la Lande A, Parisel O, Gerard H, Moliner V, Reinaud O (2008) Chem Eur J 14(21):6465–6473CrossRefGoogle Scholar
  36. 36.
    Alhambra C, Corchado J, Sanchez ML, Garcia-Viloca M, Gao J, Truhlar DG (2001) J Phys Chem B 105(45):11326–11340CrossRefGoogle Scholar
  37. 37.
    Moliner V, Turner AJ, Williams IH (1997) Chem Commun 14:1271–1272CrossRefGoogle Scholar
  38. 38.
    Turner AJ, Moliner V, Williams IH (1999) Phys Chem Chem Phys 1(6):1323–1331CrossRefGoogle Scholar
  39. 39.
    Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) J Comput Chem 4(2):187–217CrossRefGoogle Scholar
  40. 40.
    Cramer CJ, Truhlar DG (1999) Chem Rev 99(8):2161–2200CrossRefGoogle Scholar
  41. 41.
    Xue QF, Yeung ES (1995) Nature 373(6516):681–683CrossRefGoogle Scholar
  42. 42.
    Tan WH, Yeung ES (1997) Anal Chem 69(20):4242–4248CrossRefGoogle Scholar
  43. 43.
    Ranganathan S, Gready JE (1997) J Phys Chem B 101:5614–5618CrossRefGoogle Scholar
  44. 44.
    Weiner SJ, Kollman PA, Nguyen DT, Case DA (1986) J Comput Chem 7(2):230–252CrossRefGoogle Scholar
  45. 45.
    Moliner V, Williams IH (2000) Chem Commun 19:1843–1844CrossRefGoogle Scholar
  46. 46.
    Gilson MK (1993) Proteins Struct Funct Genet 15(3):266–282CrossRefGoogle Scholar
  47. 47.
    Antosiewicz J, McCammon JA, Gilson MK (1994) J Mol Biol 238(3):415–436CrossRefGoogle Scholar
  48. 48.
    Field MJ, David L, Rinaldo D. Personal CommunicationGoogle Scholar
  49. 49.
    Ferrer S, Silla E, Tuñón I, Oliva M, Moliner V, Williams IH (2005) Chem Commun 47:5873–5875CrossRefGoogle Scholar
  50. 50.
    Marti S, Moliner V, Tuñón I (2005) J Chem Theor Comput 1(5):1008–1016CrossRefGoogle Scholar
  51. 51.
    Swiderek K, Paneth P (2010) J Phys Chem B 114(9):3393–3397Google Scholar
  52. 52.
    Ferrer S, Tuñón I, Marti S, Moliner V, Garcia-Viloca M, Gonzalez-Lafont A, Lluch JM (2006) J Am Chem Soc 128(51):16851–16863CrossRefGoogle Scholar
  53. 53.
    Zhang YK, Liu HY, Yang WT (2000) J Chem Phys 112(8):3483–3492CrossRefGoogle Scholar
  54. 54.
    Schenter GK, Garrett BC, Truhlar DG (2003) J Chem Phys 119(12):5828–5833CrossRefGoogle Scholar
  55. 55.
    Roca M, Moliner V, Ruiz-Pernia JJ, Silla E, Tuñón I (2006) J Phys Chem A 110(2):503–509CrossRefGoogle Scholar
  56. 56.
    Kumar S, Bouzida D, Swendsen RH, Kollman PA, Rosenberg JM (1992) J Comput Phys 13(8):1011–1021Google Scholar
  57. 57.
    Torrie GM, Valleau JP (1977) J Comput Phys 23(2):187–199CrossRefGoogle Scholar
  58. 58.
    Kou SC, Cherayil BJ, Min W, English BP, Xie XS (2005) J Phys Chem B 109(41):19068–19081CrossRefGoogle Scholar
  59. 59.
    Smiley RD, Hammes GG (2006) Chem Rev 106(8):3080–3094CrossRefGoogle Scholar
  60. 60.
    Lu HP, Xun LY, Xie XS (1998) Science 282(5395):1877–1882CrossRefGoogle Scholar
  61. 61.
    Yang H, Luo GB, Karnchanaphanurach P, Louie TM, Rech I, Cova S, Xun LY, Xie XS (2003) Science 302(5643):262–266CrossRefGoogle Scholar
  62. 62.
    Seravalli J, Huskey WP, Schowen KB, Schowen RL (1994) Pure Appl Chem 66(4):695–702CrossRefGoogle Scholar

Copyright information

© Springer Netherlands 2010

Authors and Affiliations

  • Silvia Ferrer
    • 1
  • Sergio Martí
    • 1
  • Vicent Moliner
    • 1
    • 2
    • 3
  • Iñaki Tuñón
    • 3
  1. 1.Departament de Química Física i AnalíticaUniversitat Jaume ICastellóSpain
  2. 2.Institute of Applied Radiation ChemistryTechnical University of LodzLodzPoland
  3. 3.Departament de Química FísicaUniversitat de ValènciaBurjasotSpain

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