| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
* Laboratory of Molecular Biophysics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; and Biomolecular Modelling Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom
Correspondence: Address reprint requests to Mark S. P. Sansom, Laboratory of Molecular Biophysics, The Rex Richards Building, Dept. of Biochemistry, University of Oxford, South Parks Rd., Oxford OX1 3QU, UK. Tel.: +44-1865-275371; Fax: +44-1865-275182; E-mail: mark{at}biop.ox.ac.uk.
FhuA is one of the more complex members of the superfamily of bacterial outer membrane proteins. Its primary function is to provide a binding site on the outer membrane surface for siderophores, such as ferrichrome, and subsequently to facilitate their energy-dependent transport across the membrane, presumably powered by the TonB-ExbBD protein complex that resides in the cytoplasmic membrane. Crystal structures of FhuA with and without a bound ferrichrome molecule have provided some clues as to the initial stages of the siderophore transport mechanism. In the current study, we have employed 10-ns duration molecular dynamics simulations of FhuA and of the FhuA-ferrichrome complex, both embedded in a phospholipid bilayer, to probe the short timescale dynamics of this integral membrane protein, and to explore possible mechanistic implications of this dynamic behavior. Analysis of the dynamics of the protein suggests that the extracellular loops move as relatively rigid entities relative to the transmembrane ß-barrel. Comparison of the two simulations (with and without bound ferrichrome) revealed some ligand-induced changes in loop mobility. Specifically, loop L8 appears to be involved in a mechanism whereby the binding site is gated closed upon ligand binding. Analysis of the dynamics of water molecules within the core of the FhuA protein provided no evidence for a water-permeable protopore through which the ferrichrome might pass without a major perturbation of the FhuA protein. Overall, these simulations support the proposal that binding of ferrichrome initiates a signaling mechanism that ultimately leads to the TonB-mediated partial or total removal of the core domain from the ß-barrel, thus opening up a permeable pore. These simulations are among the longest that have been performed on a complex membrane protein. However, a simple analysis of sampling reveals that the description of protein motions is far from complete.
This article has been cited by other articles:
 |
|
 |
|
  P. D. Pawelek, N. Croteau, C. Ng-Thow-Hing, C. M. Khursigara, N. Moiseeva, M. Allaire, and J. W. Coulton Structure of TonB in complex with FhuA, E. coli outer membrane receptor. Science, June 2, 2006; 312(5778): 1399 - 1402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. A. Likic, P. R. Gooley, T. P. Speed, and E. E. Strehler A statistical approach to the interpretation of molecular dynamics simulations of calmodulin equilibrium dynamics Protein Sci., December 1, 2005; 14(12): 2955 - 2963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. A. Eisenhauer, S. Shames, P. D. Pawelek, and J. W. Coulton Siderophore Transport through Escherichia coli Outer Membrane Receptor FhuA with Disulfide-tethered Cork and Barrel Domains J. Biol. Chem., August 26, 2005; 280(34): 30574 - 30580. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Aburi and P. E. Smith Modeling and simulation of the human {delta} opioid receptor Protein Sci., August 1, 2004; 13(8): 1997 - 2008. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Endriss and V. Braun Loop Deletions Indicate Regions Important for FhuA Transport and Receptor Functions in Escherichia coli J. Bacteriol., July 15, 2004; 186(14): 4818 - 4823. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
