The effect of environment on the structure of a membrane protein: P-glycoprotein under physiological conditions

O’Mara, Megan L. and Mark, Alan E. (2012) The effect of environment on the structure of a membrane protein: P-glycoprotein under physiological conditions. Journal of Chemical Theory and Computation, 8 10: 3964-3976. doi:10.1021/ct300254y


Author O’Mara, Megan L.
Mark, Alan E.
Title The effect of environment on the structure of a membrane protein: P-glycoprotein under physiological conditions
Journal name Journal of Chemical Theory and Computation   Check publisher's open access policy
ISSN 1549-9618
1549-9626
Publication date 2012-05-28
Sub-type Article (original research)
DOI 10.1021/ct300254y
Volume 8
Issue 10
Start page 3964
End page 3976
Total pages 13
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted abstract
The stability of the crystal structure of the multidrug transporter P-glycoprotein proposed by Aller et al. (PDBid
3G5U) has been examined under different environmental conditions using molecular dynamics. We show that in the presence of
the detergent cholate, the structure of P-glycoprotein solved at pH 7.5 is stable. However, when incorporated into a cholesterolenriched
POPC membrane in the presence of 150 mM NaCl, the structure rapidly deforms. Only when the simulation
conditions closely matched the experimental conditions under which P-glycoprotein is transport active was a stable conformation
obtained. Specifically, the presence of Mg2+, which bound to distinct sites in the nucleotide binding domains (NBDs), and the
double protonation of the catalytic histidines (His583 and His1228) and His149 were required. While the structure obtained in a
membrane environment under these conditions is very similar to the crystal structure of Aller et al., there are several key
differences. The NBDs are in direct contact, reminiscent of the open state of MalK. The angle between the transmembrane
domains is also increased, resulting in an outward motion of the intracellular loops. Notably, the structures obtained from the
simulations provide a better match to a range of experimental cross-linking data than does the original 3G5U-a crystal structure.
This work highlights the effect small changes in environmental conditions can have of the conformation of a membrane protein
and the importance of representing the experimental conditions appropriately in modeling studies.
Keyword Molecular-dynamics simulations
Binding cassette transporter
Gated potassium channel
Disulfide cross-linking
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Special Issue: Wilfred F. van Gunsteren Festschrift

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 05 Nov 2012, 10:56:19 EST by Dr Megan O'mara on behalf of School of Mathematics & Physics