On April 21, 2025, the Shenzhen Medical Academy of Research and Translation (SMART) held the third SMART Lecture, welcoming Professor Eduardo Perozo, a distinguished member of the U.S. National Academy of Sciences and Professor at the Institute for Biophysical Dynamics at the University of Chicago, to deliver a compelling lecture titled "Voltage Sensing and Electromechanical Coupling in Ion Channels and Enzymes." This event was hosted by Dr. Yang Zhang, distinguished research fellow at Shenzhen Bay Laboratory (SZBL). 

Key lecture highlights based on notes recorded by SMART staff on site:

Voltage Sensing and Gating Mechanisms: From Classical Models to Frontier Advances 

Professor Perozo began his lecture with an overview of the "generalized gating cycle" of voltage-dependent ion channels, systematically illustrating the dynamic transitions between the resting, activated, and inactivated states of ion channels. He noted that since Hodgkin and Huxley proposed their mathematical model of the action potential in the 1950s, the coupling mechanism between the charge movement of the voltage sensor (S4 helix) and channel gating has remained a central research focus in the field. By elucidating the structures of canonical ion channel systems – including the Shaker potassium channel, the HCN (hyperpolarization-activated cyclic nucleotide-gated) channel, and the BK channel, his team has uncovered the diverse strategies employed by different ion channels in achieving electromechanical coupling.

Shaker potassium channel: The S4 helix triggers the rotation of the S6 helix through charge displacement, forming a hydrophobic "gating barrier." Its opening and closing mechanism relies on electrostatic interactions between charges and countercharges.

HCN channel: The movement direction of the S4 helix occurs in the opposite direction to the opening/closing polarity of the channel. Its unique elongated S4 helix enables gating under hyperpolarized conditions through a hinge-bending mechanism.

BK channel: Integrates dual regulation by voltage and calcium signals. The movement of the S4 helix acts in concert with conformational changes in the calcium-binding domain, revealing the molecular basis for the coupling between transmembrane potential and chemical signals.

Professor Perozo particularly emphasized that the recent "resolution revolution" in cryo-electron microscopy has significantly advanced the structural elucidation of ion channels in their resting states, enabling researchers for the first time to observe conformational changes in voltage sensors under transmembrane electric fields. "This breakthrough offers a brand-new perspective for understanding the dynamic behavior of ion channels in physiological conditions," he remarked.

Structural Biology and Bioengineering: From Fundamentals to Applications

Professor Perozo's team employed electrostatic engineering to introduce site-specific mutations in the voltage-sensitive phosphatase (Ci-VSP), successfully shifting the channel activation voltage by 70-100 mV. This breakthrough demonstrated the critical role of local electric fields in modulating gating charge movement. In addition, their study on the plant potassium channel Kat1 uncovered a mechanical coupling mechanism between the S4 helix and C-linker in non-domain swap channels, providing foundational insights for the design of novel biosensors.

Cross-Disciplinary Dialogue: Evolutionary Insights from Neurons to Bacteria

During the Q&A session, the audience engaged in a vibrant discussion on the molecular mechanisms of voltage sensing, the application of artificial intelligence in structural determination, and the evolutionary significance of ion channels. Professor Perozo pointed out the remarkable evolutionary conservation of voltage-dependent channels across billions of years: "From human neurons to soil bacteria, similar physicochemical solutions reveal the elegance of natural selection."

On the role of AI technologies, he remarked that "structural biology is entering 'an era of molecular pharmacology.' Future efforts will focus on elucidating more ion channel targets to pave the way for precision medicine."