The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane (SWEET, Sugars Will Eventually Be Exported Transporter). However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in the OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as for the glucose transport mechanism. SWEETs undergo a structural transition to outward-facing (OF), occluded (OC), and inward-facing (IF) and strongly support an alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly the same for OF, OC, and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and acts as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass-like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.

Balaji Selvam

Ya-Chi Yu

Li-Qing Chen

Diwakar Shukla

ACS Central Science

ACS CENTRAL SCIENCE 发表关于化学和相关领域研究的最引人注目、最重要的主要报告，其中化学方法发挥着关键作用。它也是美国化学学会出版的第一个完全开放获取的期刊。

ACS Central Science publishes the most significant and noteworthy primary reports on research in chemistry and related fields, particularly those where chemical methods play a crucial role. It is also the first fully open access journal published by the American Chemical Society.

《ACS Central Science》发表关于化学及相关领域的最重要和最引人注目的研究报告，特别是那些化学方法发挥关键作用的研究。这是美国化学学会出版的首个完全开放获取的期刊。

Molecular Basis of the Glucose Transport Mechanism in Plants

This study characterized the conformational dynamics and complete transport cycle of glucose in the OsSWEET2b transporter using extensive molecular dynamics simulations and identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and acts as an intracellularhydrophobic gate.

Category	Quartile
化学	1
化学, 化学综合	1

Molecular Basis of the Glucose Transport Mechanism in Plants

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Category	Quartile
CHEMISTRY, MULTIDISCIPLINARY	1