Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics

• DOI: 10.3389/fncel.2021.761813
• Publication Date: 2021-11-30T21:48:54Z
• Authors: Matthew L. Rook; Anna Ananchenko; Maria Musgaard; David M. MacLean
• Keywords: Acid-sensing ion channel; Linker; Aspartic acid

Structures of the trimeric acid-sensing ion channel have been solved in resting, toxin-bound open and desensitized states. Within extracellular domain, there is little difference between state state. The main exception that a loop connecting 11th 12th β-strand, just two amino acid residues long, undergoes significant functionally critical re-orientation or flipping conformations. Here we investigate how specific interactions within surrounding area influence linker stability “flipped” using all-atom molecular dynamics simulations. An inherent challenge bringing relatively slow desensitization recovery processes (in milliseconds to seconds) time window simulations (hundreds nanoseconds). To accelerate behavior, first identified mutations at either Leu414 Asn415 position with fastest kinetics followed by these mutants deprotonated state, accelerating recovery. By mutating one residue examining evolution neighbor, novel electrostatic interaction validated prior important interactions. Subsequent functional analysis corroborates findings, shedding light on factors controlling proton-mediated transitions states channel. Together, data suggest flipped stabilized from regions keeping both L414 N415 place. Interestingly, very few allow for equivalent stability. high degree sequence conservation this region therefore indicates ASIC under strong selective pressure underlines physiological importance desensitization.