Novo Nordisk Fonden - Novel Voltage-Sensing Mechanisms in Biology, derived from Principles of Soft Matter Physics

Project: Research

Project Details

Description

The sensing of transmembrane (TM) voltage differences (ΔVTM) is indispensable to key cellular functions executed by ion channels such as energy storage, signal transmission in nerves, the beating of the heart, and the sensation of heat, pain and hearing. The mechanism of voltage-sensing has been intensely investigated, and a consensus has emerged that charged voltage-sensing molecular motifs in ion channels and pumps move in response to changes in ΔVTM, thus opening or closing the channel. Here, we break from tradition to propose that ion channels employ a second mechanism to sense ΔVTM, which exploits “flexoelectricity”1 in membranes. The concept of flexoelectricity dictates that in systems with orientational order such as lipid membranes, electrical dipoles alter their orientation in response to an external electric field. Therefore, an ion channel can harness the rotation of a TM dipole, such as an alpha-helix, to generate torque and thereby sense ΔV TM. To our best knowledge, such a unique sensing mechanism has so far neither been investigated, nor discovered in biology. We propose to exploit the dipole reorientation to design novel voltage nano-sensors that can (1) sense ΔVTM in model membrane systems and (2) lead to the discovery of similar voltage-sensing motifs in proteins such as ion channels in biology. Our research can lead to the discovery of a previously unknown type of voltage-sensing mechanism in membrane proteins –and a nanosensor with potential biomedical applications. The project combines simulations at the PI's lab, and the designs will be iteratively validated using biophysical experiments in the laboratory of Tobias Weadner at Aarhus, and Arun Radhakrishnan at the University of Texas Medical Center, USA.
StatusActive
Effective start/end date01/04/202131/03/2023