Simulations of the alternating access mechanism of the sodium symporter Mhp1

Joshua L. Adelman, Amy L. Dale, Matthew C. Zwier, Divesh Bhatt, Lillian T. Chong, Daniel M. Zuckerman, Michael Grabe

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Sodium coupled cotransporters of the five-helix inverted repeat (5HIR) superfamily use an alternating access mechanism to transport a myriad of small molecules across the cell membrane. One of the primary steps in this mechanism is the conformational transition from a state poised to bind extracellular substrates to a state that is competent to deliver substrate to the cytoplasm. Here, we construct a coarse-grained model of the 5HIR benzylhydantoin transporter Mhp1 that incorporates experimental structures of the outward- and inward-open states to investigate the mechanism of this conformational change. Using the weighted ensemble path-sampling method, we rigorously sample the outward- to inward-facing transition path ensemble. The transition path ensemble reveals a heterogeneous set of pathways connecting the two states and identifies two modes of transport: one consistent with a strict alternating access mechanism and another where decoupling of the inner and outer gates causes the transient formation of a continuous permeation pathway through the transporter. We also show that the conformational switch between the outward- and inward-open states results from rigid body motions of the hash motif relative to the substrate bundle, supporting the rocking bundle hypothesis. Finally, our methodology provides the groundwork for more chemically detailed investigations of the alternating mechanism.

Original languageEnglish (US)
Pages (from-to)2399-2407
Number of pages9
JournalBiophysical Journal
Issue number10
StatePublished - Nov 16 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics


Dive into the research topics of 'Simulations of the alternating access mechanism of the sodium symporter Mhp1'. Together they form a unique fingerprint.

Cite this