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Sugar Transport across Lactose Permease Probed by Steered Molecular Dynamics

Morten Ø. Jensen ^* , Ying Yin ^* , Emad Tajkhorshid ^*  and Klaus Schulten ^* 

^* Theoretical and Computational Biophysics Group, Beckman Institute, Department of Physics, and Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois USA; and Department of Life Sciences and Chemistry, Roskilde University, Roskilde, Denmark

Correspondence: Address reprint requests to Klaus Schulten, E-mail: kschulte{at}ks.uiuc.edu.

Escherichia coli lactose permease (LacY) transports sugar across the inner membrane of the bacterium using the proton motive force to accumulate sugar in the cytosol. We have probed lactose conduction across LacY using steered molecular dynamics, permitting us to follow molecular and energetic details of lactose interaction with the lumen of LacY during its permeation. Lactose induces a widening of the narrowest parts of the channel during permeation, the widening being largest within the periplasmic half-channel. During permeation, the water-filled lumen of LacY only partially hydrates lactose, forcing it to interact with channel lining residues. Lactose forms a multitude of direct sugar-channel hydrogen bonds, predominantly with residues of the flexible N-domain, which is known to contribute a major part of LacY's affinity for lactose. In the periplasmic half-channel lactose predominantly interacts with hydrophobic channel lining residues, whereas in the cytoplasmic half-channel key protein-substrate interactions are mediated by ionic residues. A major energy barrier against transport is found within a tight segment of the periplasmic half-channel where sugar hydration is minimal and protein-sugar interaction maximal. Upon unbinding from the binding pocket, lactose undergoes a rotation to permeate either half-channel with its long axis aligned parallel to the channel axis. The results hint at the possibility of a transport mechanism, in which lactose permeates LacY through a narrow periplasmic half-channel and a wide cytoplasmic half-channel, the opening of which is controlled by changes in protonation states of key protein side groups.

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