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Flexibility in a Drug Transport Accessory Protein: Molecular Dynamics Simulations of MexA

Loredana Vaccaro ^*, Vassilis Koronakis  and Mark S. P. Sansom ^*

^* Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; and Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom

Correspondence: Address reprint requests to Mark S. P. Sansom, Tel.: 44-1865-275371; Fax: 44-1865-275273; E-mail: mark.sansom{at}bioch.ox.ac.uk.

Drug resistance in Gram-negative bacteria may be conferred via efflux through a tripartite complex of an inner membrane pump, an outer membrane pore, and a periplasmic adaptor protein. These are AcrB, TolC, and AcrA, respectively, in Escherichia coli. In Pseudomonas aerugonisa, their homologs are MexB, OprM, and MexA. Defining the interdomain 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 to determine such interdomain 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.