The Cardiac Function Summer Seminar series is holding a talk on Thursday 14th August 2025, with our invited external speaker Professor Christopher Johnson, The Johnson Laboratory, Mississippi State University, USA.
Talk Title: All-Atom Ion Channel Models Explore Allosteric Communication Between Cytosolic Events and Amino Acids that Govern Ion Conduction
Talk Time: 12:30 – 13:30 UK time
Location: Hybrid Meeting (Hybrid – online Via Teams and Meeting room 427/428 4th Floor ICTEM, Hammersmith Campus, Du Cane Road W12 0NN
Please note the seminar organizers and the Head of Section would like to request that attendees will in the majority of cases be physically present in the seminar room and a participation via Teams shall be the exception.
Research Summary:
Developing descriptions of ion channel biophysics & understanding how accessory proteins and enzymes aid or impair ion conduction.
Techniques that we commonly use: Molecular Dynamic Simulations, Recombinant Protein Production, Solution NMR, X-ray Crystallography, Fluorescence Spectroscopy, Isothermal Titration Calorimetry, Whole Cell Patch Clamp Electrophysiology, and Calcium Imaging of Isolated Cardiomycoytes.
Talk Description:
Voltage-gated ion channels (NaVs and CaVs) are complex macromolecular proteins that generate the upstroke of an action potential in excitable cells. Appropriate function is necessary for many physiological processes such as a heartbeat (NaV1.5 and CaV1.2), voluntary muscle contraction (NaV1.4), nerve conduction and neurological function (NaV1.2 and NaV1.6). Dysfunction can have debilitating and/or life-threatening consequences. Mechanistic understanding of the allosteric communication between cytosolic portions of these channels and amino acids that govern ion conduction are lacking and areas of significant interest. During the past decade, there have been several advancements with ion channel structural characterization by CryoEM; yet descriptions of extracellular and cytosolic components are often lacking. Many investigations have biophysically characterized reconstituted cytosolic components and their interactions, however, extrapolating the structural alterations and allosteric communication within a full-length intact ion channel can be challenging.To address this, my group has developed a series of all-atom models of human ion channels (NaVs and CaVs) in lipid bilayers with explicit salt and water. Leveraging the latest advancements of the AMBER forcefield (ff19sb and Lipid21) and water model (OPC), our simulations contain descriptions of cytosolic components that are poorly predicted by AlphaFold and lacking in many CryoEM structures. Our simulations improved prediction of protein backbone torsion angles and consider structural details across time (four independent one microsecond simulations for each model). I will describe our predicted cytosolic features relative to the simulated lipid bilayer. Emphasis will be placed on describing lipid protein contacts and how these can differ between ion channels located in the heart relative to ion channels from other parts of the body. We have also leveraged our improved models to explore antiarrhythmic small molecule interactions (lidocaine, mexiletine, flecainide, ranolazine) and their influence on allosteric communication. Our modeling efforts highlight the “lipid buoyancy” of ion channel amphipathic helices as a potential mechanism for allosteric communication between cytosolic events (post translational modification, accessory protein interactions, and / or disease associated mutations) and amino acids that govern ion permeation (activation gate, inactivation gate, and selectivity filter).
If you are joining online and you have not yet signed up to join the Cardiac Function Seminar Team group in order to participate in the seminar online please register via the linked tab or here which will provide access to the Team.
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The Cardiac Function Seminar Team
(Prof. Thomas Brand, Natasha Richmond)