Biophysical Chemistry 2001, Imperial College London, 19-21 Sept.2001 -  Lecture
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Marc Baaden

Abstract
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Modelling the FepA protein, a bacterial iron transporter in the outer membrane
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FepA, the receptor for ferric enterobactin-iron in E. coli, is
representative of a wider family of bacterial outer membrane proteins
mediating the active transport of ferric siderophores through the
outer membrane of Gram-negative bacteria (Roosenberg 2000).

Such transporters are possible targets for novel anti-bacterial drugs,
as inhibition of transport could be used to impede bacterial growth.
Although X-ray diffraction studies have provided a high resolution
structure of FepA (Buchanan et al.), alternative approaches such as
molecular dynamics (MD) simulations are needed to probe the
conformational dynamics of this molecule, requiring an adequate
all-atom model.

Starting from Buchanan et al.'s crystal structure, a complete
atomistic model of the full FepA apoprotein is developed in several
steps. Homology modelling is required to fix missing sidechains and
residues, pKa calculations shine light upon the probable protonation
state of ionizable residues, and Grand Canonical Monte Carlo
simulations provide insight into the hydration of the barrel interior.
The latter method is able to reproduce crystal waters and effectively
predict water positions not resolved in the crystal structure, as well
as to address the question of water density inside the pore.

References
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Buchanan, S. K.; Smith, B. S.; Venkatramani, L.; Xia, D.; Essar, L.;
Palnitkar, M.; Chakraborty, R.; van der Helm, D. and Deisenhofer, J.;
1999. Crystal structure of the outer membrane active transporter FepA
from Escherichia coli. Nature Struct. Biol. 6:56-63.

Roosenberg, J. M. 2nd; Lin, Y. M.; Lu, Y. and Miller, M. J.; 2000.
Studies and syntheses of siderophores, microbial iron chelators, and
analogs as potential drug delivery agents. Curr. Med. Chem. 7:159-97.