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

Megan L. O'Mara, Alan E. Mark*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)


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 cholesterol-enriched 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 Mg 2+, 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.

Original languageEnglish
Pages (from-to)3964-3976
Number of pages13
JournalJournal of Chemical Theory and Computation
Issue number10
Publication statusPublished - 9 Oct 2012
Externally publishedYes


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