Jing Li, Saher A. Shaikh, Giray Enkavi, Po-Chao Wen, Zhijian Huang, and Emad
Tajkhorshid.
Transient formation of water-conducting states in membrane
transporters.
Proceedings of the National Academy of Sciences, USA,
110:7696-7701, 2013.
(PMC: PMC3651479)
LI2013-ET
Membrane transporters rely on highly coordinated structural transitions between major
conformational states for their function, to prevent simultaneous access of the substrate
binding site to both sides of the membrane—a mode of operation known as the alternating
access model. Although this mechanism successfully accounts for the efficient exchange of
the primary substrate across the membrane, accruing evidence on significant water
transport and even uncoupled ion transport mediated by transporters has challenged the
concept of perfect mechanical coupling and coordination of the gating mechanism in
transporters, which might be expected from the alternating access model. Here, we present
a large set of extended equilibrium molecular dynamics simulations performed on several
classes of membrane transporters in different conformational states, to test the presence
of the phenomenon in diverse transporter classes and to investigate the underlying
molecular mechanism of water transport through membrane transporters. The simulations
reveal spontaneous formation of transient water-conducting (channel-like) states allowing
passive water diffusion through the lumen of the transporters. These channel-like states
are permeable to water but occluded to substrate, thereby not hindering the uphill
transport of the primary substrate, i.e., the alternating access model remains applicable to
the substrate. The rise of such water-conducting states during the large-scale structural
transitions of the transporter protein is indicative of imperfections in the coordinated
closing and opening motions of the cytoplasmic and extracellular gates. We propose that
the observed water-conducting states likely represent a universal phenomenon in
membrane transporters, which is consistent with their reliance on large-scale motion for
function.
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