Chemistry of cation hydration and conduction in a skeletal muscle ryanodine receptor

Abstract

AbstractRyanodine receptors (RyRs) are Ca2+-regulated Ca2+channels of 2.2-megadalton in muscles and neurons for calcium signaling. How Ca2+regulates ion conduction in the RyR channels remains elusive. We determined a 2.6-Å cryo-EM structure of rabbit skeletal muscle RyR1, and used multiscale dynamics simulations to elucidate cation interactions with RyR1. We investigated 21 potential cation-binding sites that may together rationalize biphasic Ca2+response of RyR1. The selectivity filter captures a cation hydration complex by hydrogen-bonding with both the inner and outer hydration shells of water molecules. Molecular dynamics simulations suggest that adjacent Ca2+ions moving in concert along ion-permeation pathway are separated by at least two cation-binding sites. Our analysis reveals that RyR1 has been evolved to favor its interactions with two hydration shells of cations.