Abbreviations: ABC transporter, ATP binding cassette transporter; MD, molecular dynamics; NBD, nucleotide binding domain; NB site, nucleotide binding site; P-gp, P-glycoprotein; QZ59-RRR, cyclic-tris-(R)-valineselnazole; QZ59-SSS, cyclic- tris-(S)-valineselnazole; TMD, transmembrane domain.
Substrate versus inhibitor dynamics of P-glycoprotein
Article first published online: 17 JUN 2013
Copyright © 2013 Wiley Periodicals, Inc.
Proteins: Structure, Function, and Bioinformatics
Volume 81, Issue 9, pages 1653–1668, September 2013
How to Cite
Ma, J. and Biggin, P. C. (2013), Substrate versus inhibitor dynamics of P-glycoprotein. Proteins, 81: 1653–1668. doi: 10.1002/prot.24324
- Issue published online: 23 AUG 2013
- Article first published online: 17 JUN 2013
- Accepted manuscript online: 13 MAY 2013 10:05PM EST
- Manuscript Accepted: 19 APR 2013
- Manuscript Revised: 24 MAR 2013
- Manuscript Received: 17 JAN 2013
- molecular dynamics;
- multi-drug resistance;
By far the most studied multidrug resistance protein is P-glycoprotein. Despite recent structural data, key questions about its function remain. P-glycoprotein (P-gp) is flexible and undergoes large conformational changes as part of its function and in this respect, details not only of the export cycle, but also the recognition stage are currently lacking. Given the flexibility, molecular dynamics (MD) simulations provide an ideal tool to examine this aspect in detail. We have performed MD simulations to examine the behaviour of P-gp. In agreement with previous reports, we found that P-gp undergoes large conformational changes which tended to result in the nucleotide-binding domains coming closer together. In all simulations, the approach of the NBDs was asymmetrical in agreement with previous observations for other ABC transporter proteins. To validate the simulations, we make extensive comparison to previous cross-linking data. Our results show very good agreement with the available data. We then went on to compare the influence of inhibitor compounds bound with simulations of a substrate (daunorubicin) bound. Our results suggest that inhibitors may work by keeping the NBDs apart, thus preventing ATP-hydrolysis. On the other hand, repeat simulations of daunorubicin (substrate) in one particular binding pose suggest that the approach of the NBDs is not impaired and that the structure would be still be competent to perform ATP hydrolysis, thus providing a model for inhibition or substrate transport. Finally we compare the latter to earlier QSAR data to provide a model for the first part of substrate transport within P-gp. Proteins 2013. © 2013 Wiley Periodicals, Inc.