BIOPHYSICAL THEORY AND MODELING |
FLEXIBILITY IN A DRUG TRANSPORT ACCESSORY PROTEIN: MOLECULAR DYNAMICS SIMULATIONS OF MEXA
Loredana Vaccaro 1, Vassilis Koronakis 2 and Mark Sansom 3*
1 Univ Oxford
2 Univ of Cambridge
3 University of Oxford
* To whom correspondence should be addressed. E-mail: mark{at}biop.ox.ac.uk.
Submitted on December 20, 2005
Revised on January 30, 2006
Accepted on 18 April 2006
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Abstract |
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Drug resistance in Gram negative bacteria may be conferred via efflux through a tri-partite complex of an inner membrane pump, an outer membrane pore, and a periplasmic adaptor protein. These are AcrB, TolC and AcrA respectively in E. coli. In Pseudomonas aerugonisa their homologues are MexB, OprM, and MexA. Defining the inter-domain dynamics of the adaptor protein is essential to understanding the mechanism of complex formation. Extended (25 ns) molecular dynamics simulations of MexA have been performed in order to determine such inter-domain dynamics. Analysis of conformational drift demonstrates substantial motions of the three domains of MexA relative to one another. Principal components analysis reveals a hinge-bending motion, and rotation of the 
-helical hairpin relative to the other domains, to be the two dominant motions. These two motions provide an element of considerable flexibility which is likely to be exploited in the adaptor function of MexA.
Key Words:
MexA, adaptor protein, drug resistance, membrane transport, molecular dynamics, principal components analysis
