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.