Seminar by Prof. Vincenzo Carnevale
Temple University (Philadelphia, USA)
For decades, the activation of voltage-gated ion channels has been a subject of intense research, leading to an atomically detailed understanding of the major conformational changes at the molecular level. Despite this comprehensive knowledge, recent experimental findings have revealed a surprising collective behavior: in physiological membranes, voltage-gated ion channels not only form clusters but also exhibit cooperative gating. In this presentation, I will introduce a quantitative theory that seamlessly connects these disparate length scales, resolving the apparent contradiction between individual and collective channel behaviors. This novel framework, grounded in the statistical physics of immiscible fluids, provides insights into the formation of lipid rafts and their influence on the conformation of ion channels within them. I will begin by discussing extensive coarse grain simulations over long timescales. These simulations reveal a distinct compositional bias in annular lipids, which varies between resting and activated states of the channels. The data from these simulations will be instrumental in estimating channel-lipid interactions, thereby parameterizing a mesoscopic model. This model will enable us to examine the spatial distribution of ion channels and their dynamic response to changes in transmembrane potential. A key finding I will present is that channels in membranes near a miscibility transition exhibit attractive long-range interactions, leading to clustering. Intriguingly, the lipid phase behavior is also influenced by the activation state of the ion channels. This interplay results in strong activation cooperativity and prolonged hysteresis effects, offering a potential explanation for the modal gating phenomena frequently observed in single-channel recordings. By shedding light on these complex phenomena, these results offer a novel perspective on the functioning of ion channels in physiological environments.