Skip to main content
SpringerLink
Log in

Computational Modeling of Biological Systems: The LDH Story

  • Chapter
  • First Online:
Kinetics and Dynamics

Part of the book series: Challenges and Advances in Computational Chemistry and Physics ((COCH,volume 12))

  • 1645 Accesses

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Ertl G, Gloyna T (2003) Zeitschrift Fur Physikalische Chemie-Int J Res Phys Chem Chem Phys 217(10):1207–1219

    Article  CAS  Google Scholar 

  2. Ostwald W (1902) Phys Z 3:313–322

    Google Scholar 

  3. Ostwald W (1910) Ann Naturphil 9:1

    Google Scholar 

  4. Corma A (2004) Cat Rev Sci Eng 46(3–4):369–417

    Article  CAS  Google Scholar 

  5. Garcia-Viloca M, Gao J, Karplus M, Truhlar DG (2004) Science 303(5655):186–195

    Article  CAS  Google Scholar 

  6. Warshel A, Sharma PK, Kato M, Xiang Y, Liu HB, Olsson MHM (2006) Chem Rev 106(8):3210–3235

    Article  CAS  Google Scholar 

  7. Truhlar DG (2008) J Am Chem Soc 130(50):16824–16827

    Article  CAS  Google Scholar 

  8. Field MJ (2007) A practical introduction to the simulation of molecular systems. Cambridge University Press, Cambridge

    Book  Google Scholar 

  9. Warshel A, Levitt M (1976) J Mol Biol 103(2):227–249

    Article  CAS  Google Scholar 

  10. Kollman P (1993) Chem Rev 93(7):2395–2417

    Article  CAS  Google Scholar 

  11. Kollman PA, Kuhn B, Donini O, Perakyla M, Stanton R, Bakowies D (2001) Acc Chem Res 34(1):72–79

    Article  CAS  Google Scholar 

  12. Marti S, Andres J, Moliner V, Silla E, Tuñón I, Bertran J, Field MJ (2001) J Am Chem Soc 123(8):1709–1712

    Article  CAS  Google Scholar 

  13. Marti S, Roca M, Andres J, Moliner V, Silla E, Tuñón I, Bertran J (2004) Chem Soc Rev 33(2):98–107

    Article  CAS  Google Scholar 

  14. Marti S, Andres J, Moliner V, Silla E, Tuñón I, Bertran J (2008) Chem Soc Rev 37(12):2634–2643

    Article  CAS  Google Scholar 

  15. Gao JL, Truhlar DG (2002) Annu Rev Phys Chem 53:467–505

    Article  CAS  Google Scholar 

  16. Villa J, Warshel A (2001) J Phys Chem B 105(33):7887–7907

    Article  CAS  Google Scholar 

  17. Warshel A (1998) J Biol Chem 273(42):27035–27038

    Article  CAS  Google Scholar 

  18. Lin H, Truhlar DG (2007) Theor Chem Acc 117(2):185–199

    Article  CAS  Google Scholar 

  19. Clarke AR, Wigley DB, Chia WN, Barstow D, Atkinson T, Holbrook JJ (1986) Nature 324(6098):699–702

    Article  CAS  Google Scholar 

  20. Hart KW, Clarke AR, Wigley DB, Chia WN, Barstow DA, Atkinson T, Holbrook JJ (1987) Biochem Biophys Res Commun 146(1):346–353

    Article  CAS  Google Scholar 

  21. Clarke AR, Atkinson T, Holbrook JJ (1989) Biochem Sci 14:145–148

    Article  CAS  Google Scholar 

  22. Badcoe IG, Smith CJ, Wood S, Halsall DJ, Holbrook JJ, Lund P, Clarke AR (1991) Biochemistry 30(38):9195–9200

    Article  CAS  Google Scholar 

  23. Deng H, Zheng J, Clarke A, Holbrook JJ, Callender R, Burgner JW (1994) Biochemistry 33(8):2297–2305

    Article  CAS  Google Scholar 

  24. Clarke AR, Wigley DB, Barstow DA, Chia WN, Waldman ADB, Hart KW, Atkinson T, Holbrook JJ (1987) Biochem Soc Trans 15(1):152–153

    CAS  Google Scholar 

  25. Andres J, Moliner V, Krechl J, Silla E (1993) Bioorg Chem 21(3):260–274

    Article  CAS  Google Scholar 

  26. Andres J, Moliner V, Safont VS (1994) J Chem Soc Faraday Trans 90(12):1703–1707

    Article  CAS  Google Scholar 

  27. Andres J, Moliner V, Krechl J, Silla E (1995) J Chem Soc Perkin Trans 2(7):1551–1558

    Google Scholar 

  28. Krechl J, Kuthan J (1988) Theochem J Mol Struct 47:239–244

    Article  CAS  Google Scholar 

  29. Wilkie J, Williams IH (1992) J Am Chem Soc 114(13):5423–5425

    Article  CAS  Google Scholar 

  30. Wilkie J, Williams IH (1995) J Chem Soc Perkin Trans 2(7):1559–1567

    Google Scholar 

  31. Ranganathan S, Gready JE (1994) J Chem Soc Farad Trans 90(14):2047–2056

    Article  CAS  Google Scholar 

  32. Yadav A, Jackson RM, Holbrook JJ, Warshel A (1991) J Am Chem Soc 113(13):4800–4805

    Article  CAS  Google Scholar 

  33. Siegbahn PEM, Himo F (2009) J Biol Inorg Chem 14(5):643–651

    Article  CAS  Google Scholar 

  34. de la Lande A, Gerard H, Moliner V, Izzet G, Reinaud O, Parisel O (2006) J Biol Inorg Chem 11(5):593–608

    Article  CAS  Google Scholar 

  35. de la Lande A, Parisel O, Gerard H, Moliner V, Reinaud O (2008) Chem Eur J 14(21):6465–6473

    Article  Google Scholar 

  36. Alhambra C, Corchado J, Sanchez ML, Garcia-Viloca M, Gao J, Truhlar DG (2001) J Phys Chem B 105(45):11326–11340

    Article  CAS  Google Scholar 

  37. Moliner V, Turner AJ, Williams IH (1997) Chem Commun 14:1271–1272

    Article  Google Scholar 

  38. Turner AJ, Moliner V, Williams IH (1999) Phys Chem Chem Phys 1(6):1323–1331

    Article  CAS  Google Scholar 

  39. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983) J Comput Chem 4(2):187–217

    Article  CAS  Google Scholar 

  40. Cramer CJ, Truhlar DG (1999) Chem Rev 99(8):2161–2200

    Article  CAS  Google Scholar 

  41. Xue QF, Yeung ES (1995) Nature 373(6516):681–683

    Article  CAS  Google Scholar 

  42. Tan WH, Yeung ES (1997) Anal Chem 69(20):4242–4248

    Article  CAS  Google Scholar 

  43. Ranganathan S, Gready JE (1997) J Phys Chem B 101:5614–5618

    Article  CAS  Google Scholar 

  44. Weiner SJ, Kollman PA, Nguyen DT, Case DA (1986) J Comput Chem 7(2):230–252

    Article  CAS  Google Scholar 

  45. Moliner V, Williams IH (2000) Chem Commun 19:1843–1844

    Article  Google Scholar 

  46. Gilson MK (1993) Proteins Struct Funct Genet 15(3):266–282

    Article  CAS  Google Scholar 

  47. Antosiewicz J, McCammon JA, Gilson MK (1994) J Mol Biol 238(3):415–436

    Article  CAS  Google Scholar 

  48. Field MJ, David L, Rinaldo D. Personal Communication

    Google Scholar 

  49. Ferrer S, Silla E, Tuñón I, Oliva M, Moliner V, Williams IH (2005) Chem Commun 47:5873–5875

    Article  Google Scholar 

  50. Marti S, Moliner V, Tuñón I (2005) J Chem Theor Comput 1(5):1008–1016

    Article  CAS  Google Scholar 

  51. Swiderek K, Paneth P (2010) J Phys Chem B 114(9):3393–3397

    Google Scholar 

  52. Ferrer S, Tuñón I, Marti S, Moliner V, Garcia-Viloca M, Gonzalez-Lafont A, Lluch JM (2006) J Am Chem Soc 128(51):16851–16863

    Article  CAS  Google Scholar 

  53. Zhang YK, Liu HY, Yang WT (2000) J Chem Phys 112(8):3483–3492

    Article  CAS  Google Scholar 

  54. Schenter GK, Garrett BC, Truhlar DG (2003) J Chem Phys 119(12):5828–5833

    Article  CAS  Google Scholar 

  55. Roca M, Moliner V, Ruiz-Pernia JJ, Silla E, Tuñón I (2006) J Phys Chem A 110(2):503–509

    Article  CAS  Google Scholar 

  56. Kumar S, Bouzida D, Swendsen RH, Kollman PA, Rosenberg JM (1992) J Comput Phys 13(8):1011–1021

    CAS  Google Scholar 

  57. Torrie GM, Valleau JP (1977) J Comput Phys 23(2):187–199

    Article  Google Scholar 

  58. Kou SC, Cherayil BJ, Min W, English BP, Xie XS (2005) J Phys Chem B 109(41):19068–19081

    Article  CAS  Google Scholar 

  59. Smiley RD, Hammes GG (2006) Chem Rev 106(8):3080–3094

    Article  CAS  Google Scholar 

  60. Lu HP, Xun LY, Xie XS (1998) Science 282(5395):1877–1882

    Article  CAS  Google Scholar 

  61. Yang H, Luo GB, Karnchanaphanurach P, Louie TM, Rech I, Cova S, Xun LY, Xie XS (2003) Science 302(5643):262–266

    Article  CAS  Google Scholar 

  62. Seravalli J, Huskey WP, Schowen KB, Schowen RL (1994) Pure Appl Chem 66(4):695–702

    Article  CAS  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Departament de Química Física i Analítica, Universitat Jaume I, 12071, Castelló, Spain

    Silvia Ferrer, Sergio Martí & Vicent Moliner

  2. Institute of Applied Radiation Chemistry, Technical University of Lodz, 90-924, Lodz, Poland

    Vicent Moliner

  3. Departament de Química Física, Universitat de València, 46100, Burjasot, Spain

    Vicent Moliner & Iñaki Tuñón

Authors
  1. Silvia Ferrer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sergio Martí
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vicent Moliner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Iñaki Tuñón
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Inst. Applied Radiation Chemistry, Dept. Chemistry, Technical University of Lodz, Zeromskiego 116, Lodz, 90-924, Poland

    Piotr Paneth

  2. Inst. Applied Radiation Chemistry, Dept. Chemistry, Technical University of Lodz, Zeromskiego 116, Lodz, 90-924, Poland

    Agnieszka Dybala-Defratyka

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Netherlands

About this chapter

Cite this chapter

Ferrer, S., Martí, S., Moliner, V., Tuñón, I. (2010). Computational Modeling of Biological Systems: The LDH Story. In: Paneth, P., Dybala-Defratyka, A. (eds) Kinetics and Dynamics. Challenges and Advances in Computational Chemistry and Physics, vol 12. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3034-4_13

Download citation

Publish with us

Policies and ethics

Search

Navigation