Functional Mechanisms of ABC Transporters as Revealed by Molecular Simulations

  • Tadaomi Furuta
  • Minoru SakuraiEmail author


Active transport in cells is accomplished by a class of integral membrane proteins known as ATP-binding cassette (ABC) transporters. The energy source powering these molecular machines is the free energy generated by the binding of ATP molecules to nucleotide-binding domains (NBDs), as well as the free energy generated by ATP hydrolysis. The opening and closing motions of the NBDs are driven by these energies, which are propagated through transmembrane domains (TMDs) via mechanical transmission segments (coupling helices). As a result, the opening and closing motions of the TMDs are generated, which allow the uptake and release of substrates. In these processes, the chemical energy of ATP is converted into mechanical motion, a typical example of chemo-mechanical coupling. In this review, we describe the current understanding of this coupling mechanism, with a focus on the cooperative role of ATP and water.


ATP Water Chemo-mechanical coupling ATPase 



This work was supported in part by JSPS KAKENHI JP16H00825, JP16K12520, and JP15K00400. We cordially thank Mr. Sho Tanaka for his contribution to the calculated data shown in Tables 12.1 and 12.2.


  1. Ahmad M, Gu W, Geyer T, Helms V (2011) Adhesive water networks facilitate binding of protein interfaces. Nat Commun 2:261CrossRefGoogle Scholar
  2. Arai N, Furuta T, Sakurai M (2017) Analysis of an ATP-induced conformational transition of ABC transporter MsbA using a coarse-grained model. Biophys Physicobiol 14:161–171CrossRefGoogle Scholar
  3. Ben-Naim A (2006) On the driving forces for protein-protein association. J Chem Phys 125:024901CrossRefGoogle Scholar
  4. Chang S-Y, Liu F-F, Dong X-Y, Sun Y (2013) Molecular insight into conformational transmission of human P-glycoprotein. J Chem Phys 139:225102CrossRefGoogle Scholar
  5. Changeux J-P, Edelstein S (2011) Conformational selection or induced fit? 50 years of debate resolved. F1000 Biol Rep 3:19Google Scholar
  6. Chen HL, Gabrilovich D, Tampe R, Girgis KR, Nadaf S, Carbone DP (1996) A functionally defective allele of TAP1 results in loss of MHC class I antigen presentation in a human lung cancer. Nat Genet 13:210–213CrossRefGoogle Scholar
  7. Chen J (2013) Molecular mechanism of the Escherichia coli maltose transporter. Curr Opin Struct Biol 23:492–498CrossRefGoogle Scholar
  8. Colvin ME, Evleth E, Akacem Y (1995) Quantum chemical studies of pyrophosphate hydrolysis. J Am Chem Soc 117:4357–4362CrossRefGoogle Scholar
  9. Cui J, Davidson AL (2011) ABC solute importers in bacteria. Essays Biochem 50:85–99CrossRefGoogle Scholar
  10. Düttmann M, Togashi Y, Yanagida T, Mikhailov Alexander S (2012) Myosin-V as a mechanical sensor: an elastic network study. Biophys J 102:542–551CrossRefGoogle Scholar
  11. Dassa E, Bouige P (2001) The ABC of ABCs: a phylogenetic and functional classification of ABC systems in living organisms. Res Microbiol 152:211–229CrossRefGoogle Scholar
  12. Davidson AL, Dassa E, Orelle C, Chen J (2008) Structure, function, and evolution of bacterial atp-binding cassette systems. Microbiol Mol Biol Rev 72:317–364CrossRefGoogle Scholar
  13. Dawson RJP, Locher KP (2006) Structure of a bacterial multidrug ABC transporter. Nature 443:180–185CrossRefGoogle Scholar
  14. Dawson RJP, Locher KP (2007) Structure of the multidrug ABC transporter Sav 1866 from Staphylococcus aureus in complex with AMP-PNP. FEBS Lett 581:935–938CrossRefGoogle Scholar
  15. Ferreira RJ, Bonito CA, Ferreira MJU, dos Santos DJVA (2017) About P-glycoprotein: a new drugable domain is emerging from structural data. WIREs Comput Mol Sci 7:e1316CrossRefGoogle Scholar
  16. Ferreira RJ, Ferreira M-JU, dos Santos DJVA (2015) Reversing cancer multidrug resistance: insights into the efflux by ABC transports from in silico studies. WIREs Comput Mol Sci 5:27–55CrossRefGoogle Scholar
  17. Fletcher JI, Haber M, Henderson MJ, Norris MD (2010) ABC transporters in cancer: more than just drug efflux pumps. Nat Rev Cancer 10:147–156CrossRefGoogle Scholar
  18. Furukawa-Hagiya T, Furuta T, Chiba S, Sohma Y, Sakurai M (2013) The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations. J Phys Chem B 117:83–93CrossRefGoogle Scholar
  19. Furukawa-Hagiya T, Yoshida N, Chiba S, Hayashi T, Furuta T, Sohma Y, Sakurai M (2014) Water-mediated forces between the nucleotide binding domains generate the power stroke in an ABC transporter. Chem Phys Lett 616–617:165–170CrossRefGoogle Scholar
  20. Furuta T, Sato Y, Sakurai M (2016) Structural dynamics of the heterodimeric ABC transporter TM287/288 induced by ATP and substrate binding. Biochemistry 55:6730–6738CrossRefGoogle Scholar
  21. Furuta T, Yamaguchi T, Kato H, Sakurai M (2014) Analysis of the structural and functional roles of coupling helices in the ATP-binding cassette transporter MsbA through enzyme assays and molecular dynamics simulations. Biochemistry 53:4261–4272CrossRefGoogle Scholar
  22. George AM, Jones PM (2012) Perspectives on the structure–function of ABC transporters: the switch and constant contact models. Prog Biophys Mol Biol 109:95–107CrossRefGoogle Scholar
  23. George P, Witonsky RJ, Trachtman M, Wu C, Dorwart W, Richman L, Richman W, Shurayh F, Lentz B (1970) “Squiggle-H2O”. An enquiry into the importance of solvation effects in phosphate ester and anhydride reactions. Biochim Biophys Acta 223:1–15CrossRefGoogle Scholar
  24. Grigorenko BL, Rogov AV, Nemukhin AV (2006) Mechanism of triphosphate hydrolysis in aqueous solution: QM/MM simulations in water clusters. J Phys Chem B 110:4407–4412CrossRefGoogle Scholar
  25. Hamelberg D, Mongan J, McCammon JA (2004) Accelerated molecular dynamics: a promising and efficient simulation method for biomolecules. J Chem Phys 120:11919–11929CrossRefGoogle Scholar
  26. Harrison CB, Schulten K (2012) Quantum and classical dynamics simulations of ATP hydrolysis in solution. J Chem Theory Comput 8:2328–2335CrossRefGoogle Scholar
  27. Hatzakis NS (2014) Single molecule insights on conformational selection and induced fit mechanism. Biophys Chem 186:46–54CrossRefGoogle Scholar
  28. Hayashi T, Chiba S, Kaneta Y, Furuta T, Sakurai M (2014) ATP-induced conformational changes of nucleotide-binding domains in an ABC transporter. Importance of the water-mediated entropic force. J Phys Chem B 118:12612–12620CrossRefGoogle Scholar
  29. Hayes DM, Kenyon GL, Kollman PA (1978) Theoretical calculations of the hydrolysis energies of some “high-energy” molecules. 2. A survey of some biologically important hydrolytic reactions. J Am Chem Soc 100:4331–4340CrossRefGoogle Scholar
  30. Higgins CF, Linton KJ (2004) The ATP switch model for ABC transporters. Nat Struct Mol Biol 11:918–926CrossRefGoogle Scholar
  31. Hollenstein K, Dawson RJP, Locher KP (2007) Structure and mechanism of ABC transporter proteins. Curr Opin Struct Biol 17:412–418CrossRefGoogle Scholar
  32. Hsu W-L, Furuta T, Sakurai M (2018) The mechanism of nucleotide-binding domain dimerization in the intact maltose transporter as studied by all-atom molecular dynamics simulations. Proteins 86:237–247CrossRefGoogle Scholar
  33. Hsu W-L, Furuta T, Sakurai M (2015) Analysis of the free energy landscapes for the opening-closing dynamics of the maltose transporter ATPase MalK2 using enhanced-sampling molecular dynamics simulation. J Phys Chem B 119:9717–9725CrossRefGoogle Scholar
  34. Hsu W-L, Furuta T, Sakurai M (2016) ATP hydrolysis mechanism in a maltose transporter explored by QM/MM metadynamics simulation. J Phys Chem B 120:11102–11112CrossRefGoogle Scholar
  35. Huang W, Liao J-L (2016) Catalytic mechanism of the maltose transporter hydrolyzing ATP. Biochemistry 55:224–231CrossRefGoogle Scholar
  36. Jardetzky O (1966) Simple allosteric model for membrane pumps. Nature 211:969CrossRefGoogle Scholar
  37. Kamerlin SCL, Florián J, Warshel A (2008) Associative versus dissociative mechanisms of phosphate monoester hydrolysis: on the interpretation of activation entropies. ChemPhysChem 9:1767–1773CrossRefGoogle Scholar
  38. Kiani FA, Fischer S (2016) Comparing the catalytic strategy of ATP hydrolysis in biomolecular motors. Phys Chem Chem Phys 18:20219–20233CrossRefGoogle Scholar
  39. Klähn M, Rosta E, Warshel A (2006) On the mechanism of hydrolysis of phosphate monoesters dianions in solutions and proteins. J Am Chem Soc 128:15310–15323CrossRefGoogle Scholar
  40. Knowles JR (1980) Enzyme-catalyzed phosphoryl transfer reactions. Annu Rev Biochem 49:877–919CrossRefGoogle Scholar
  41. Li CH, Yang YX, Su JG, Liu B, Tan JJ, Zhang XY, Wang CX (2014) Allosteric transitions of the maltose transporter studied by an elastic network model. Biopolymers 101:758–768CrossRefGoogle Scholar
  42. Liu H, Li D, Li Y, Hou T (2016) Atomistic molecular dynamics simulations of ATP-binding cassette transporters. WIREs Comput Mol Sci 6:255–265CrossRefGoogle Scholar
  43. Locher KP (2016) Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat Struct Mol Biol 23:487–493CrossRefGoogle Scholar
  44. Lomovskaya O, Zgurskaya HI, Totrov M, Watkins WJ (2007) Waltzing transporters and ‘the dance macabre’ between humans and bacteria. Nat Rev Drug Discov 6:56–65CrossRefGoogle Scholar
  45. Loo TW, Bartlett MC, Clarke DM (2013) Human P-glycoprotein Contains a greasy ball-and-socket joint at the second transmission interface. J Biol Chem 288:20326–20333CrossRefGoogle Scholar
  46. Markwick PRL, McCammon JA (2011) Studying functional dynamics in bio-molecules using accelerated molecular dynamics. Phys Chem Chem Phys 13:20053–20065CrossRefGoogle Scholar
  47. McDevitt CA, Crowley E, Hobbs G, Starr KJ, Kerr ID, Callaghan R (2008) Is ATP binding responsible for initiating drug translocation by the multidrug transporter ABCG2? FEBS J 275:4354–4362CrossRefGoogle Scholar
  48. Moitra K, Dean M (2011) Evolution of ABC transporters by gene duplication and their role in human disease. Biol Chem 392:29–37CrossRefGoogle Scholar
  49. Molinski S, Eckford P, Pasyk S, Ahmadi S, Chin S, Bear C (2012) Functional rescue of F508del-CFTR using small molecule correctors. Front Pharmacol 3Google Scholar
  50. Moradi M, Tajkhorshid E (2013) Mechanistic picture for conformational transition of a membrane transporter at atomic resolution. Proc Natl Acad Sci USA 110:18916–18921CrossRefGoogle Scholar
  51. Moradi M, Tajkhorshid E (2014) Computational recipe for efficient description of large-scale conformational changes in biomolecular systems. J Chem Theory Comput 10:2866–2880CrossRefGoogle Scholar
  52. Mourez M, Hofnung M, Dassa E (1997) Subunit interactions in ABC transporters: a conserved sequence in hydrophobic membrane proteins of periplasmic permeases defines an important site of interaction with the ATPase subunits. EMBO J 16:3066–3077CrossRefGoogle Scholar
  53. Netlson DL, Cox MC (2005) Lehninger: principles of biochemistry, 4th edn. W. H. Freeman and Company, New YorkGoogle Scholar
  54. Oancea G, O’Mara ML, Bennett WFD, Tieleman DP, Abele R, Tampé R (2009) Structural arrangement of the transmission interface in the antigen ABC transport complex TAP. Proc Natl Acad Sci USA 106:5551–5556CrossRefGoogle Scholar
  55. Oldham ML, Chen J (2011) Crystal structure of the maltose transporter in a pretranslocation intermediate state. Science 332:1202–1205CrossRefGoogle Scholar
  56. Oldham ML, Khare D, Quiocho FA, Davidson AL, Chen J (2007) Crystal structure of a catalytic intermediate of the maltose transporter. Nature 450:515CrossRefGoogle Scholar
  57. Oliveira ASF, Baptista AM, Soares CM (2011) Inter-domain communication mechanisms in an ABC importer: a molecular dynamics study of the MalFGK2E complex. PLoS Comput Biol 7:e1002128CrossRefGoogle Scholar
  58. Perez C, Gerber S, Boilevin J, Bucher M, Darbre T, Aebi M, Reymond J-L, Locher KP (2015) Structure and mechanism of an active lipid-linked oligosaccharide flippase. Nature 524:433CrossRefGoogle Scholar
  59. Prasad BR, Plotnikov NV, Warshel A (2013) Addressing open questions about phosphate hydrolysis pathways by careful free energy mapping. J Phys Chem B 117:153–163CrossRefGoogle Scholar
  60. Sakaizawa H, Watanabe HC, Furuta T, Sakurai M (2016) Thermal fluctuations enable rapid protein–protein associations in aqueous solution by lowering the reaction barrier. Chem Phys Lett 643:114–118CrossRefGoogle Scholar
  61. Schlitter J, Engels M, Krüger P, Jacoby E, Wollmer A (1993) Targeted molecular dynamics simulation of conformational change-application to the T↔R transition in insulin. Mol Simul 10:291–308CrossRefGoogle Scholar
  62. Shilton Brian H (2015) Active transporters as enzymes: an energetic framework applied to major facilitator superfamily and ABC importer systems. Biochem J 467:193–199CrossRefGoogle Scholar
  63. Smith PC, Karpowich N, Millen L, Moody JE, Rosen J, Thomas PJ, Hunt JF (2002) ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol Cell 10:139–149CrossRefGoogle Scholar
  64. Subramanian N, Condic-Jurkic K, O’Mara ML (2016) Structural and dynamic perspectives on the promiscuous transport activity of P-glycoprotein. Neurochem Int 98:146–152CrossRefGoogle Scholar
  65. Szakács G, Váradi A, Özvegy-Laczka C, Sarkadi B (2008) The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME–Tox). Drug Discov Today 13:379–393CrossRefGoogle Scholar
  66. Takahashi H, Umino S, Miki Y, Ishizuka R, Maeda S, Morita A, Suzuki M, Matubayasi N (2017) Drastic compensation of electronic and solvation effects on ATP hydrolysis revealed through large-scale QM/MM simulations combined with a theory of solutions. J Phys Chem B 121:2279–2287CrossRefGoogle Scholar
  67. Tirion MM (1996) Large amplitude elastic motions in proteins from a single-parameter, atomic analysis. Phys Rev Lett 77:1905–1908CrossRefGoogle Scholar
  68. Ulucan O, Jaitly T, Helms V (2014) Energetics of hydrophilic protein-protein association and the role of water. J Chem Theory Comput 10:3512–3524CrossRefGoogle Scholar
  69. Wang C, Huang W, Liao J-L (2015) QM/MM investigation of ATP hydrolysis in aqueous solution. J Phys Chem B 119:3720–3726CrossRefGoogle Scholar
  70. Wang Z, Liao J-L (2015) Probing structural determinants of ATP-binding cassette exporter conformational transition using coarse-grained molecular dynamics. J Phys Chem B 119:1295–1301CrossRefGoogle Scholar
  71. Watanabe Y, Hsu W-L, Chiba S, Hayashi T, Furuta T, Sakurai M (2013) Dynamics and structural changes induced by ATP and/or substrate binding in the inward-facing conformation state of P-glycoprotein. Chem Phys Lett 557:145–149CrossRefGoogle Scholar
  72. Weng J-W, Fan K-N, Wang W-N (2010) The conformational transition pathway of ATP binding cassette transporter MsbA revealed by atomistic simulations. J Biol Chem 285:3053–3063CrossRefGoogle Scholar
  73. Weng J, Gu S, Gao X, Huang X, Wang W (2017) Maltose-binding protein effectively stabilizes the partially closed conformation of the ATP-binding cassette transporter MalFGK2. Phys Chem Chem Phys 19:9366–9373CrossRefGoogle Scholar
  74. Xie XL, Li CH, Yang YX, Jin L, Tan JJ, Zhang XY, Su JG, Wang CX (2015) Allosteric transitions of ATP-binding cassette transporter MsbA studied by the adaptive anisotropic network model. Proteins 83:1643–1653CrossRefGoogle Scholar
  75. Xu Y, Seelig A, Bernèche S (2017) Unidirectional transport mechanism in an ATP dependent exporter. ACS Cent Sci 3:250–258CrossRefGoogle Scholar
  76. Yamamoto T (2010) Preferred dissociative mechanism of phosphate monoester hydrolysis in low dielectric environments. Chem Phys Lett 500:263–266CrossRefGoogle Scholar
  77. Yoshida N (2014) Efficient implementation of the three-dimensional reference interaction site model method in the fragment molecular orbital method. J Chem Phys 140:214118CrossRefGoogle Scholar
  78. Yoshidome T, Kinoshita M, Hirota S, Baden N, Terazima M (2008) Thermodynamics of apoplastocyanin folding: comparison between experimental and theoretical results. J Chem Phys 128:225104CrossRefGoogle Scholar
  79. Zaitseva J, Jenewein S, Jumpertz T, Holland IB, Schmitt L (2005) H662 is the linchpin of ATP hydrolysis in the nucleotide-binding domain of the ABC transporter HlyB. EMBO J 24:1901–1910CrossRefGoogle Scholar
  80. Zhou Y, Ojeda-May P, Pu J (2013) H-loop histidine catalyzes ATP hydrolysis in the E. coli ABC-transporter HlyB. Phys Chem Chem Phys 15:15811–15815CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  1. 1.Center for Biological Resources and InformaticsTokyo Institute of TechnologyTokyoJapan

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