Molecular Determinants of Mg²⁺-Mediated Inhibition in RyR1: Insights from Computational Approaches.

ABSTRACT: We investigated Mg²⁺-mediated inhibition of RyR1 by analyzing solvation, permeation, and binding interactions of Mg²⁺, Ca²⁺, Na⁺, and K⁺ across three functional states: Ca²⁺-activated (opRyR1), closed (clRyR1), and Mg²⁺-inhibited (HMg²⁺RyR1). Using molecular dynamics simulations, potential of mean force (PMF) analysis, quantum mechanical calculations, and MM-GBSA binding free energy calculations, we identified the structural and energetic determinants of Mg²⁺ inhibition. Our water occupancy analysis reveals that Mg²⁺ binding at D4945 stabilizes the S6 helical arrangement within the cytoplasmic vestibule in the HMg²⁺RyR1 state, maintaining a narrowed pore and reducing wat

SUBMITTER: Boonamnaj P 

PROVIDER: S-EPMC12290639 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature