Molecular simulations meet personalized medicine: The mechanism of action of CLC-5 antiporter and the origin of Dent's disease

ClC-5 is a Cl-/H+ antiporter crucial for the homeostasis of the entire organism, and whose functional deficiencies cause pathologies such as Dent's disease, a rare genetic disorder that can have lethal consequences. While the clinical aspects of the pathology are known, its molecular basis is elusive, which hampers the development of potential therapies. We present here a systematic study, where we explore the mechanism of transport of ClC-5, deciphering the choreography of structural changes required for the transport of chloride ions and protons in opposing directions. Once the mechanism is determined, we explore how the 523ΔVal deletion linked to Dent's disease hampers the correct functioning of the transporter, despite having a very minor structural impact. Our study highlights how state-of-the-art simulation methods can shed light on the origin of rare diseases and explore targets for personalized medicine.