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Detailed Mechanism for AmtB Conducting NH₄⁺/NH₃: Molecular Dynamics Simulations

Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Science and Graduate School, Chinese Academy of Sciences, Shanghai 201203, China

Correspondence: Address reprint requests to Weiliang Zhu or Hualiang Jiang, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, 555 Zuchongzhi Road, Shanghai 201203, China. Tel.: 86-21-5080-5020; Fax: 86-21-5080-7088; E-mail: wlzhu{at}mail.shcnc.ac.cn; hljiang{at}mail.shcnc.ac.cn.

The mechanism by which the ammonium transporter, AmtB, conducts into the cytoplasm was investigated using conventional molecular dynamics (MD) simulations. These simulations revealed that the neutral molecule, NH₃, passes automatically through the channel upon its arrival at the Am2 site and that the function of the channel as a one-way valve for passage of NH₃ is not determined by the cytoplasmic exit gate but, rather, by the periplasmic entrance gate of the channel. The NH₃, produced by deprotonation of at the entrance gate, is spontaneously conveyed to the central region of the channel via a hydrogen-bond network comprising His-168, His-318, Tyr-32, and the NH₃ molecule. Finally, the NH₃ molecule exits the channel through the exit gate formed by Phe-31, Ile-266, Val-314, and His-318. In addition, Ser-263 is shown to play a critical role in the final stages, acting as a pivoting arm to shunt the NH₃ molecule from the cytoplasmic exit gate of the channel out into the cytoplasm. This finding is further supported by another simulation which shows that NH₃ fails to be translocated through the channel formed by the Ser-263–Ala mutation. Thus, this study casts new insights on the mechanism of AmtB-mediated passage of NH₃ across cellular membranes.

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