Abstract
ATP-binding cassette (ABC) transporters are ATP-driven molecular machines. ATP binding and hydrolysis in the nucleotide-binding domains (NBDs) are coupled to large-scale conformational changes of the transmembrane domains (TMDs), which leads to the translocation of substrate molecules across biological membranes. The atomic details of the structural dynamics underlying the conformational transitions and the coupling of NBD and TMD motions remained largely terra incognita. Here, we used all-atom molecular dynamics (MD) simulations to characterize the conformational transitions underlying the working cycle of the heterodimeric ABC exporter TM287/288 from Thermotoga maritima. Multi-microsecond MD simulations reveal how ATP binding triggers a spontaneous conformational transition from the initial inward-facing (IF) conformation via an occluded (Occ) intermediate to an outward-facing (OF) conformation. ATP binding induces tightening of the NBD dimer, which involves closing and reorientation of the two NBD monomers. Simultaneous closure of the cytoplasmic (intracellular) TMD gate region leads to the Occ state. Subsequent wide opening of the periplasmic (extracellular) TMD gate yields the OF conformer. This distinct sequence of events imposes tight coupling of NBDs and TMDs and ensures that the cytoplasmic and periplasmic TMD gates are not open at the same time to both sides of the membrane.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
A.L. Davidson, E. Dassa, C. Orelle, J. Chen, Microbiol. Mol. Biol. Rev. 72(2), 317 (2008)
C.F. Higgins, Nature 446, 749 (2007)
K.P. Locher, Nat. Struct. Mol. Biol. 23, 487 (2016)
M. Hohl, C. Briand, M.G. Grütter, M.A. Seeger, Nat. Struct. Mol. Biol. 19(4), 395 (2012)
M. Hohl, L.M. Hürlimann, S. Bohm, J. Schoppe, M.G. Grütter, E. Bordignon, M.A. Seeger, Proc. Natl. Acad. Sci. USA 111, 11025 (2014)
M. Prieß, H. Göddeke, G. Groenhof, L.V. Schäfer, ACS Cent. Sci. 4(10), 1334 (2018)
E. Lindahl, M.S.P. Sansom, Curr. Opin. Struct. Biol. 18(4), 425 (2008)
J. Li, P.C. Wen, M. Moradi, E. Tajkhorshid, Curr. Opin. Struct. Biol. 31, 96 (2015)
D.C. Gadsby, P. Vergani, L. Csanády, Nature 440, 477 (2006)
D. Parcej, R. Tampé, Nat. Chem. Biol. 6(8), 572 (2010)
R. Huber, T.A. Langworthy, H. König, M. Thomm, C.R. Woese, U.B. Sleytr, K.O. Stetter, Arch. Microbiol. 144(4), 324 (1986)
M.H. Timachi, C.A. Hutter, M. Hohl, T. Assafa, S. Bohm, A. Mittal, M.A. Seeger, E. Bordignon,eLife 6, e20236 (2017)
H. Göddeke, M.H. Timachi, C.A.J. Hutter, L. Galazzo, M.A. Seeger, M. Karttunen, E. Bordignon, L.V. Schäfer, J. Am. Chem. Soc. 140(13), 4543 (2018)
C.A.J. Hutter, M.H. Timachi, L.M. Hürlimann, I. Zimmermann, P. Egloff, H. Göddeke, S. Kucher, S. Stefanic, M. Karttunen, L.V. Schäfer, E. Bordignon, M.A. Seeger, Nat. Commun. 10, 2260 (2019)
M.J. Abraham, M. Murtola, R. Schulz, S. Páll, J.C. Smith, B. Hess, E. Lindahl, SoftwareX 1–2, 19 (2015)
V. Hornak, R. Abel, A. Okur, B. Strockbine, A. Roitberg, C. Simmerling, Proteins 65, 712 (2006)
K. Lindorff-Larsen, S. Piana, K. Palmo, P. Maragakis, J.L. Klepeis, R.O. Dror, Proteins 78, 1950 (2010)
O. Berger, O. Edholm, F. Jähnig, Biophys. J. 72, 2002 (1997)
K.L. Meagher, L.T. Redman, H.A. Carlson, J. Comput. Chem. 24(9), 1016 (2003)
C. Kandt, W.L. Ash, D.P. Tieleman, Methods 41, 475 (2007)
J.L.F. Abascal, C. Vega, J. Chem. Phys. 123, 234505 (2005)
S. Páll, B. Hess, Comput. Phys. Commun. 184(12), 2641 (2013)
U. Essmann, L. Perera, M.L. Berkowitz, T. Darden, H. Lee, L.G. Pedersen, J. Chem. Phys. 103(19), 8577 (1995)
S. Miyamoto, P.A. Kollman, J. Comput. Chem. 13, 952 (1993)
B. Hess, J. Chem. Theory Comput. 4, 116 (2008)
K.A. Feenstra, B. Hess, H.J.C. Berendsen, J. Comput. Chem. 20(8), 786 (1999)
G. Bussi, D. Donadio, M. Parrinello, J. Chem. Phys. 126, 014101 (2007)
C.F. Higgins, K.J. Linton, Nat. Struct. Mol. Biol. 11, 918 (2004)
Acknowledgements
The Steinbuch Centre for Computing (SCC) in Karlsruhe is acknowledged for providing computational resources. This work was funded by the Deutsche Forschungsgemeinschaft (DFG) through an Emmy Noether grant to L.S. (SCHA 1574/3-1) and Cluster of Excellence RESOLV (EXC-2033) project number 390677874.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this paper
Cite this paper
Göddeke, H., Schäfer, L. (2021). Atomistic Dynamics of Alternating Access Mechanism of an ABC Transporter. In: Nagel, W.E., Kröner, D.H., Resch, M.M. (eds) High Performance Computing in Science and Engineering '19. Springer, Cham. https://doi.org/10.1007/978-3-030-66792-4_8
Download citation
DOI: https://doi.org/10.1007/978-3-030-66792-4_8
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-030-66791-7
Online ISBN: 978-3-030-66792-4
eBook Packages: Mathematics and StatisticsMathematics and Statistics (R0)