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Molecular basis of P450 OleTJE: an investigation of substrate binding mechanism and major pathways

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Abstract

Cytochrome P450 OleTJE has attracted much attention for its ability to catalyze the decarboxylation of long chain fatty acids to generate alkenes, which are not only biofuel molecule, but also can be used broadly for making lubricants, polymers and detergents. In this study, the molecular basis of the binding mechanism of P450 OleTJE for arachidic acid, myristic acid, and caprylic acid was investigated by utilizing conventional molecular dynamics simulation and binding free energy calculations. Moreover, random acceleration molecular dynamics (RAMD) simulations were performed to uncover the most probable access/egress channels for different fatty acids. The predicted binding free energy shows an order of arachidic acid < myristic acid < caprylic acid. Key residues interacting with three substrates and residues specifically binding to one of them were identified. The RAMD results suggest the most likely channel for arachidic acid, myristic acid, and caprylic acid are 2e/2b, 2a and 2f/2a, respectively. It is suggested that the reaction is easier to carry out in myristic acid bound system than those in arachidic acid and caprylic acid bound system based on the distance of Hβ atom of substrate relative to P450 OleTJE Compound I states. This study provided novel insight to understand the substrate preference mechanism of P450 OleTJE and valuable information for rational enzyme design for short chain fatty acid decarboxylation.

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References

  1. Coon MJ (2005) Annu Rev Pharmacol Toxicol 45:1–25

    Article  CAS  Google Scholar 

  2. Meunier B, de Visser SP, Shaik S (2004) Chem Rev 104:3947–3980

    Article  CAS  Google Scholar 

  3. Poulos TL (2014) Chem Rev 114:3919–3962

    Article  CAS  Google Scholar 

  4. Bernhardt R (2006) J Biotechnol 124:128–145

    Article  CAS  Google Scholar 

  5. Urlacher VB, Eiben S (2006) Trends Biotechnol 24:324–330

    Article  CAS  Google Scholar 

  6. Rude MA, Baron TS, Brubaker S, Alibhai M, Del Cardayre SB, Schirmer A (2011) Appl Environ Microbiol 77:1718–1727

    Article  CAS  Google Scholar 

  7. Belcher J, McLean KJ, Matthews S, Woodward LS, Fisher K, Rigby SEJ, Nelson DR, Potts D, Baynham MT, Parker DA, Leys D, Munro AW (2014) J Biol Chem 289:6535–6550

    Article  CAS  Google Scholar 

  8. Beller H, Goh E, Keasling J (2010) Appl Environ Microbiol 76:1212–1223

    Article  CAS  Google Scholar 

  9. Schirmer A, Rude MA, Li X, Popova E, Del Cardayre SB (2010) Science 329:559–562

    Article  CAS  Google Scholar 

  10. Mendez-Perez D, Begemann M, Pfleger B (2011) Appl Environ Microbiol 77:4264–4267

    Article  CAS  Google Scholar 

  11. Liu Y, Wang C, Yan J, Zhang W, Guan W, Lu X, Li S (2014) Biotechnol Biofuels 7:28

    Article  Google Scholar 

  12. Popov YV, Uskach YL, Ledenev SM, Kroman DA, Pavlova VA (2013) Russ J Appl Chem 86:447–449

    Article  CAS  Google Scholar 

  13. Kioupis LI, Maginn EJ (1999) J Phys Chem B 103:10781–10790

    Article  CAS  Google Scholar 

  14. Srinivasan J, Cheatham TE, Cieplak P, Kollman PA, Case DA (1998) J Am Chem Soc 120:9401–9409

    Article  CAS  Google Scholar 

  15. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Acc Chem Res 33:889–897

    Article  CAS  Google Scholar 

  16. Lüdemann SK, Lounnas V, Wade RC (2000) J Mol Biol 303:813–830

    Article  Google Scholar 

  17. Wang T, Duan Y (2007) J Am Chem Soc 129:6970–6971

    Article  CAS  Google Scholar 

  18. Wang T, Duan Y (2009) J Mol Biol 392:1102–1115

    Article  CAS  Google Scholar 

  19. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) Nucleic Acids Res 28:235–242

    Article  CAS  Google Scholar 

  20. Sitkoff D, Sharp KA, Honig B (1994) J Phys Chem 98:1978–1988

    Article  CAS  Google Scholar 

  21. Bayly CI, Cieplak P, Cornell W, Kollman PA (1993) J Phys Chem 97:10269–10280

    Article  CAS  Google Scholar 

  22. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery Jr JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09v. D.01. Gaussian, Inc., Wallingford

    Google Scholar 

  23. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) J Comput Chem 25:1157–1174

    Article  CAS  Google Scholar 

  24. Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Proteins 65:712–725

    Article  CAS  Google Scholar 

  25. Oda A, Yamaotsu N, Hirono S (2005) J Comput Chem 26:818–826

    Article  CAS  Google Scholar 

  26. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  27. Coleman TG, Mesick HC, Darby RL (1977) Ann Biomed Eng 5:322–328

    Article  CAS  Google Scholar 

  28. Darden T, York D, Pedersen L (1993) J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  29. Tsui V, Case DA (2000) Biopolymers 56:275–291

    Article  CAS  Google Scholar 

  30. Genheden S, Ryde U (2015) Expert Opin Drug Discovery 10:449–461

    Article  CAS  Google Scholar 

  31. Chovancova E, Pavelka A, Benes P, Strnad O, Brezovsky J, Kozlikova B, Gora A, Sustr V, Klvana M, Medek P, Biedermannova L, Sochor J, Damborsky J (2012) PLoS Comput Biol 8:e1002708

    Article  CAS  Google Scholar 

  32. Schrödinger, LLC (2010) The PyMOL Molecular Graphics System, vol 1.3. Schrödinger, LLC, New York

    Google Scholar 

  33. Kalé L, Skeel R, Bhandarkar M, Brunner R, Gursoy A, Krawetz N, Phillips J, Shinozaki A, Varadarajan K, Schulten K (1999) J Comput Phys 151:283–312

    Article  Google Scholar 

  34. Klvana M, Pavlova M, Koudelakova T, Chaloupkova R, Dvorak P, Prokop Z, Stsiapanava A, Kuty M, Kuta-Smatanova I, Dohnalek J, Kulhanek P, Wade RC, Damborsky J (2009) J Mol Biol 392:1339–1356

    Article  CAS  Google Scholar 

  35. Fasan R, Meharenna YT, Snow CD, Poulos TL, Arnold FH (2008) J Mol Biol 383:1069–1080

    Article  CAS  Google Scholar 

  36. Cojocaru V, Winn PJ, Wade RC (2007) Biochim Biophys Acta 1770:390–401

    Article  CAS  Google Scholar 

  37. Pavlova M, Klvana M, Prokop Z, Chaloupkova R, Banas P, Otyepka M, Wade R, Tsuda M, Nagata Y, Damborsky J (2009) Nat Chem Biol 5:727–733

    Article  CAS  Google Scholar 

  38. Sehnal D, Svobodova Varekova R, Berka K, Pravda L, Navratilova V, Banas P, Ionescu C-M, Otyepka M, Koca J (2013) J Cheminform 5:39

    Article  CAS  Google Scholar 

  39. Kingsley LJ, Lill MA (2015) Proteins 83:599–611

    Article  CAS  Google Scholar 

  40. Lüdemann SK, Lounnas V, Wade RC (2000) J Mol Biol 303:797–811

    Article  Google Scholar 

  41. Li W, Liu H, Scott EE, Grater F, Halpert JR, Luo X, Shen J, Jiang H (2005) Drug Metab Dispos 33:910–919

    Article  CAS  Google Scholar 

  42. Fishelovitch D, Shaik S, Wolfson HJ, Nussinov R (2009) J Phys Chem B 113:13018–13025

    Article  CAS  Google Scholar 

  43. Li W, Shen J, Liu G, Tang Y, Hoshino T (2011) Proteins 79:271–281

    Article  CAS  Google Scholar 

  44. Winn PJ, Lüdemann SK, Gauges R, Lounnas V, Wade RC (2002) Proc Natl Acad Sci U S A 99:5361–5366

    Article  CAS  Google Scholar 

  45. Li W, Liu H, Luo X, Zhu W, Tang Y, Halpert JR, Jiang H (2007) Drug Metab Dispos 35:689–696

    Article  CAS  Google Scholar 

  46. Shen Z, Cheng F, Xu Y, Fu J, Xiao W, Shen J, Liu G, Li W, Tang Y (2012) PLoS ONE 7:e33500

    Article  CAS  Google Scholar 

  47. Cojocaru V, Winn PJ, Wade RC (2012) Curr Drug Metab 13:143–154

    Article  CAS  Google Scholar 

  48. Bai Q, Shi D, Zhang Y, Liu H, Yao X (2014) Mol BioSyst 10:1958–1967

    Article  CAS  Google Scholar 

  49. Li W, Fu J, Cheng F, Zheng M, Zhang J, Liu G, Tang Y (2012) J Chem Inf Model 52:3043–3052

    Article  CAS  Google Scholar 

  50. Kalyaanamoorthy S, Chen YPP (2012) J Chem Inf Model 52:589–603

    Article  CAS  Google Scholar 

  51. Kalyaanamoorthy S, Chen YPP (2013) J Comput Chem 34:2270–2283

    Article  CAS  Google Scholar 

  52. Lee DS, Yamada A, Sugimoto H, Matsunaga I, Ogura H, Ichihara K, Adachi SI, Park SY, Shiro Y (2003) J Biol Chem 278:9761–9767

    Article  CAS  Google Scholar 

  53. Podust LM, Poulos TL, Waterman MR (2001) Proc Natl Acad Sci U S A 98:3068–3073

    Article  CAS  Google Scholar 

  54. Grant JL, Hsieh CH, Makris TM (2015) J Am Chem Soc 137:4940–4943

    Article  CAS  Google Scholar 

  55. Faponle AS, Quesne MG, de Visser SP (2016) Chem Eur J 22:5478–5483

    Article  CAS  Google Scholar 

  56. Wang J, Hou T, Xu X (2006) Curr Comput-Aid Drug 2:287–306

    Article  CAS  Google Scholar 

  57. Zgarbova M, Otyepka M, Sponer J, Hobza P, Jurecka P (2010) Phys Chem Chem Phys 12:10476–10493

    Article  CAS  Google Scholar 

  58. Sun H, Li Y, Tian S, Xu L, Hou T (2014) Phys Chem Chem Phys 16:16719–16729

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 31300599, 21572242), the Talents of High Level Scientific Research Foundation (Grant Nos. 6631113318, 6631113326) and Initial Foundation for Doctors (Grant No. 6631112308) of Qingdao Agricultural University and the Natural Science Foundation of Shandong Province, China (Grant No. ZR2015BM021).

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Authors and Affiliations

  1. Key Lab of Applied Mycology, College of Life Science, Qingdao Agricultural University, Qingdao, 266109, China

    Juan Du, Lin Liu, Li Zhong Guo & Jian Ming Yang

  2. College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, China

    Xiao Jun Yao

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Du, J., Liu, L., Guo, L.Z. et al. Molecular basis of P450 OleTJE: an investigation of substrate binding mechanism and major pathways. J Comput Aided Mol Des 31, 483–495 (2017). https://doi.org/10.1007/s10822-017-0013-x

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  • DOI: https://doi.org/10.1007/s10822-017-0013-x

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