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Nucleotide-Dependent Conformational Changes in HisP: Molecular Dynamics Simulations of an ABC Transporter Nucleotide-Binding Domain

Jeff D. Campbell ^* , Sundeep Singh Deol ^*, Frances M. Ashcroft , Ian D. Kerr  and Mark S. P. Sansom ^*

^* Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom; School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom; and University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom

Correspondence: Address reprint requests to Mark S. P. Sansom, Tel.: 44-1865-275371; Fax: 44-1865-275182; E-mail: mark.sansom{at}biop.ox.ac.uk.

ATP-binding cassette (ABC) transporters mediate the movement of molecules across cell membranes in both prokaryotes and eukaryotes. In ABC transporters, solute translocation occurs after ATP is either bound or hydrolyzed at the intracellular nucleotide-binding domains (NBDs). Molecular dynamics (MD) simulations have been employed to study the interactions of nucleotide with NBD. The results of extended (20 ns) MD simulations of HisP (total simulation time 80 ns), the NBD of the histidine transporter HisQMP₂J from Salmonella typhimurium, are presented. Analysis of the MD trajectories reveals conformational changes within HisP that are dependent on the presence of ATP in the binding pocket of the protein, and are sensitive to the presence/absence of Mg ions bound to the ATP. These changes are predominantly confined to the -helical subdomain of HisP. Specifically there is a rotation of three -helices within the subdomain, and a movement of the signature sequence toward the bound nucleotide. In addition, there is considerable conformational flexibility in a conserved glutamine-containing loop, which is situated at the interface between the -helical subdomain and the F1-like subdomain. These results support the mechanism for ATP-induced conformational transitions derived from the crystal structures of other NBDs.

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