Simulation Studies of the Mechanism of Membrane Transporters

  • Giray Enkavi
  • Jing Li
  • Paween Mahinthichaichan
  • Po-Chao Wen
  • Zhijian Huang
  • Saher A. Shaikh
  • Emad Tajkhorshid
Part of the Methods in Molecular Biology book series (MIMB, volume 924)


Membrane transporters facilitate active transport of their specific substrates, often against their electrochemical gradients across the membrane, through coupling the process to various sources of cellular energy, for example, ATP binding and hydrolysis in primary transporters, and pre-established electrochemical gradient of molecular species other than the substrate in the case of secondary transporters. In order to provide efficient energy-coupling mechanisms, membrane transporters have evolved into molecular machines in which stepwise binding, translocation, and transformation of various molecular species are closely coupled to protein conformational changes that take the transporter from one functional state to another during the transport cycle. Furthermore, in order to prevent the formation of leaky states and to be able to pump the substrate against its electrochemical gradient, all membrane transporters use the widely-accepted “alternating access mechanism,” which ensures that the substrate is only accessible from one side of the membrane at a given time, but relies on complex and usually global protein conformational changes that differ for each family of membrane transporters. Describing the protein conformational changes of different natures and magnitudes is therefore at the heart of mechanistic studies of membrane transporters. Here, using a number of membrane transporters from diverse families, we present common protocols used in setting up and performing molecular dynamics simulations of membrane transporters and in analyzing the results, in order to characterize relevant motions of the system. The emphasis will be on highlighting how optimal design of molecular dynamics simulations combined with mechanistically oriented analysis can shed light onto key functionally relevant protein conformational changes in this family of membrane proteins.

Key words

Alternating access mechanism Molecular dynamics Conformational change Conformational coupling Outward-facing (OF) state Inward-facing (IF) state Occluded state State transition ABC transporters Maltose transporter Nucleotide binding domains (NBDs) ATP hydrolysis Biased simulation Na+ -coupled galactose transporter Ion release Substrate release Betaine Glycerol-3-phosphate (G3P) Inorganic phosphate (PiMajor facilitator superfamily (MFS) Transmembrane helices Protonation state Titration state Apo state Rocker-switch model Salt bridge Normal mode analysis (NMA) Anisotropic network model (ANM) Glycerol-3-phosphate transporter (GlpT) Glutamate transporter Primary transporter Secondary transporter Extracellular gate Intracellular gate Coupling Dipole moment Na+ /betaine symporter (BetP) Binding pocket Binding site Solvent-accessible Putative binding site Unbinding pathway 



The studies reported in this review were supported by grants from NIH (R01-GM086749, R01-GM067887, and P41-RR05969). The authors acknowledge computer time at TeraGrid resources (grant number MCA06N060), as well as computer time from the DoD High Performance Computing Modernization Program at the Arctic Region Supercomputing Center, University of Alaska at Fairbanks.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Giray Enkavi
    • 1
  • Jing Li
    • 1
  • Paween Mahinthichaichan
    • 1
  • Po-Chao Wen
    • 1
  • Zhijian Huang
    • 1
  • Saher A. Shaikh
    • 1
  • Emad Tajkhorshid
    • 1
  1. 1.Department of Biochemistry, Center for Biophysics and Computational Biology, College of Medicine, Beckman Institute for Advanced Science and TechnologyUniversity of Illinois at Urbana-ChampaignUrbanaUSA

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