Simulation of ion permeation using the novel method described in the publication. Credit by: Wojciech Kopec
Nearly 50 years after the invention of the patch-clamp technique revolutionised our understanding of electrical signalling in cells, scientists have achieved a major milestone: accurately simulating the minute electric currents that flow through ion channels using atom-by-atom computational models.
In a study published in PNAS, researchers from the Max Planck Institute (MPI) for Multidisciplinary Sciences and Queen Mary University of London have used advanced molecular dynamics simulations to replicate, with quantitative precision, the ion currents previously measured in laboratory experiments. This marks the first time such agreement has been achieved between computational predictions and patch-clamp electrophysiological data – a gold standard in biophysics since the 1970s.
"With this work, we can finally peer into the channel with atomic detail and truly understand what's going on as ions pass through," said Dr Wojciech Kopec, Lecturer in Computational Pharmaceutical Chemistry at Queen Mary University of London and co-author of the study.
Ion channels are essential proteins embedded in cell membranes that control the flow of charged particles, like potassium or sodium ions, enabling processes from nerve signalling to heartbeat regulation. While patch-clamp recordings have allowed scientists to measure the electrical activity of single ion channels since 1976 – a feat that earned a Nobel Prize in 1991 – they have not revealed exactly how ions move through these molecular gates.
Using powerful simulations that include electronic polarisation effects, the research team discovered something remarkable: up to four potassium ions line up in the channel "like pearls on a string" – packed side by side, rather than separated by water molecules as previously assumed.
"This is counterintuitive," explained first author Chenggong Hui from Max Planck Institute for Multidisciplinary Sciences. "Positively charged ions should repel each other, but this tightly packed configuration turns out to be key to the channel's exceptional speed and selectivity."
The findings settle a decades-long scientific debate and help clarify how ion channels achieve both rapid conduction and exquisite selectivity – able to favour potassium over the slightly smaller sodium ion.
Beyond the fundamental insight, the implications are wide-ranging. The new approach could reshape how we study drug interactions with ion channels, which are common targets in treatments for pain, epilepsy, and heart conditions. Future applications include designing more effective ion channel modulators or better understanding how mutations in these proteins lead to disease.
The study is also a poignant nod to the legacy of the late George Sheldrick, who first suggested – through crystallographic data – that ions might align in such a fashion within the channel. This new work confirms and extends his pioneering insights with dynamic, real-time simulations.
"This is a technological and conceptual leap forward," added Dr Kopec. "Being able to simulate ion flow with this level of accuracy opens up entirely new avenues for studying physiology and developing therapeutics. In fact, we are currently applying our newly developed method to study cardiotoxicity of several drug candidates, in collaboration with Janssen Pharmaceutica."
