Biophysical Society Conference | Tahoe 2023

Proton Reactions: From Basic Science to Biomedical Applications

Wednesday Speaker Abstracts

LEARNING ABOUT PROPERTIES OF THE VOLTAGE-GATED PROTON CHANNEL FROM IN SILICO METHODS Christophe Jardin 1 ; Gustavo Chaves 1 ; Niklas Ohlwein 1,2 ; Boris Musset 1 ; 1 Klinikum Nürnberg Medical School, Paracelsus Medical University, Center of Physiology, Pathophysiology and Biophysics (CPPB), Nuremberg, Germany 2 Universitätklinik der Paracelsus Medizinischen Privatuniversität, b. Klinik für Anästhesiologie und operative Intensivmedizin, Nuremberg, Germany Voltage-gated proton channels are key players in a multitude of physiological processes, widely distributed in human and many other organisms. The H V proton channels are atypical channels, to date probably the most unique in the superfamily of voltage-gated ion channels. They are the most selective ion channels described so far (almost perfectly selective for hydrogen ions), their activity is dependent on the voltage across the membrane, and this voltage-dependence is strongly controlled by the pH gradient across the membrane. Unlike traditional ion channels, like K V or Na V channels, that have one domain formed by four transmembrane helices, S1 to S4, for voltage-sensing and one pore domain, with two transmembrane helices S5 and S6, through which the ions transit, the voltage-sensing and pore domains of HV channels are fused in one single domain, S1-S4. The main function of proton channels is to extrude (with only a few exceptions) protons from the cytoplasm, thereby regulating the intracellular pH. Since the identification of the HVCN1 gene in 2006, some progress has been made in understanding the molecular determinants of H V channel’s properties from experimental studies. However, still little is known about how the structure of the channel accomplishes its functions. In fact, many of the known aspects of H V channel functions have been clarified using in silico methods. In our lab, besides patch-clamp experiments, we use such methods, e.g. molecular dynamics simulations, to investigate properties of H V channels. We will show that the application of these methods allowed us to unveil the structural determinants of, e.g., the binding of Zn 2+ cations, that inhibit the channels, or the pH-dependent gating in the case of the human voltage-gated proton channel.

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