Biophysical Society Thematic Meeting | Trieste 2024

Emerging Theoretical Approaches to Complement Single-Particle Cryo-EM

Poster Abstracts

14-POS Board 14 KIR CHANNEL DYNAMICS REVEALED BY MOLECULAR DYNAMICS SIMULATIONS Sun Joo Lee 1 ; Eva-Maria Zangerl-Plessl 2 ; Anna Stary-Weinzinger 2 ; Nichols G Nichols 1 ; 1 Washington University in St. Louis, Department of Cell Biology and Physiology, Saint Louis, MO, USA 2 University of Vienna, Division of Pharmacology and Toxicology, Vienna, Australia Inwardly rectifying potassium (Kir) channels are important regulators of membrane potential in both excitable and non-excitable cells. Various diseases arise from aberrant Kir channel activities, which are controlled by a complex interplay of regulatory lipids, small molecules, and auxiliary proteins. Despite recent advancements in cryo-electron microscopy (EM) that have greatly enhanced our understanding of Kir channel structures, their conformational dynamics remain elusive. This study employs atomistic molecular dynamics (MD) simulations in order to 1) unveil intrinsic conformational dynamics of Kir2.1 channels and 2) elucidate how these dynamics are modulated by the primary agonist, phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ). The simulations show that PI(4,5)P 2 potentiates a clockwise twisting motion in the cytoplasmic domain of each subunit, leading to opening of the channel at a gate formed by the four TM2 helices at the bottom of each transmembrane domain, consistent with a recent EM based structure of PI(4,5)P 2 -bound open Kir6.2 channel. PI(4,5)P 2 also suppresses intrinsic 2 fold anticorrelated motions between the two pairs of diagonally opposed subunits while enhancing positive correlation among all four subunits, thus facilitating channel opening and explaining the basis of cooperative gating by PI(4,5)P 2 . In conclusion, the atomistic MD simulations reveal the intrinsic conformational dynamics of Kir channels and demonstrate how the primary agonist modulates these dynamics, collectively facilitating channel opening.

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