Nanomachine-Assisted Ion Transport Across Membranes: From Mechanism to Rational Design and Applications

Assisting
ion transport across membranes by means of sophisticated
molecular machines has promising applications in the treatment of
diseases induced by dysregulated ion transport. To develop such nanoscale
devices imbued with specific functions, rational de novo design, upstream from costly syntheses, is eminently desirable but
would require the atomic detail of the translocation mechanism, which
is still largely missing. We have explored the full ion capture–transport–release
process over an aggregate simulation time of 60 μs, employing
leading-edge enhanced-sampling algorithms to disentangle with unprecedented
detail the mechanism that underlies ion transport mediated by a membrane-spanning
[2]­rotaxane composed of an ion carrier linked to a wheel threaded
onto an axle. Beyond validating the reliability of our methodology
through careful examination of the clockwork of a documented nanomachine,
we put forth an original pH-controlled nano-object that can assist
transient unidirectional ion transport across membranes.