S. A. Shaikh and E. Tajkhorshid.
Potential cation and H+ binding sites in acid sensing ion
channel-1.
Biophysical Journal, 95:5153-5164, 2008.
(PMC: 2586576)
SHAI2008-ET
Acid sensing ion channels (ASICs) are cation-selective membrane channels activated by H1 binding upon
decrease in extracellular pH. It is known that Ca21 plays an important modulatory role in ASIC gating, competing with the ligand
(H1) for its binding site(s). However, the H1 or Ca21 binding sites involved in gating and the gating mechanism are not fully known.
Wecarried out a computational study to investigate potential cation andH1binding sites for ASIC1 via all-atom molecular dynamics
simulations on five systems. The systems were designed to test the candidacy of some acid sensing residues proposed from
experiment and to determine yet unknown ligand binding sites. The ion binding patterns reveal sites of cation (Na1 and Ca21)
localization where they may compete with protons and influence channel gating. The highest incidence of Ca21 and Na1 binding is
observed at a highly acidic pocket on the protein surface. Also, Na1 ions fill in an inner chamber that contains a ring of acidic
residues and that is near the channel entrance; this site could possibly be a temporary reservoir involved in ion permeation. Some
acidic residues were observed to orient and move significantly close together to bind Ca21, indicating the structural consequences
of Ca21 release from these sites. Local structural changes in the protein due to cation binding or ligand binding (protonation) are
examined at the binding sites and discussed. This study provides structural and dynamic details to test hypotheses for the role of
Ca21 and Na1 ions in the channel gating mechanism.
