Multiscale molecular dynamics simulations predict arachidonic acid binding sites in human ASIC1a and ASIC3 transmembrane domains

Abstract

Acid-sensing ion channels (ASICs) play important roles in inflammatory pathways by conducting ions across the neuronal membrane in response to proton binding under acidic conditions. Recent studies have shown that ASICs can be modulated by arachidonic acid (AA), and, in the case of the ASIC3 subtype, even activated by AA at physiological pH. However, the mechanism by which these fatty acids act on the channel is still unknown. Here, we have used multiscale molecular dynamics simulations to predict a putative, general binding region of AA to models of the human ASIC protein. We have identified, in agreement with recent studies, residues in the outer leaflet transmembrane region which interact with AA. In addition, despite their similar modulation, we observe subtle differences in the AA interaction pattern between human ASIC1a and human ASIC3, which can be reversed by mutating three key residues at the outer leaflet portion of TM1. We further probed interactions with these residues in hASIC3 using atomistic simulations and identified possible AA coordinating interactions; salt bridge interactions of AA with R65hASIC3 and R68hASIC3 and AA tail interactions with the Y58hASIC3 aromatic ring. We have shown that longer fatty acid tails with more double bonds have increased relative occupancy in this region of the channel, a finding supported by recent functional studies. We further proposed that the modulatory effect of AA on ASIC does not result from changes in local membrane curvature. Rather, we speculate that it may occur through structural changes to the ion channel upon AA binding.

State-dependent binding of cholesterol and an anionic lipid to the muscle-type Torpedo nicotinic acetylcholine receptor

“…Individual frames from CG-MD simulations can be back-mapped to all-atom structures for simulations that shed light on the nature of the lipid-protein associations. MD simulations have been used to study lipid binding to a variety of pLGICs 35 , with multi-timescale simulation approaches recently applied to the neuronal α7 nAChR 40 , glycine receptor 41 , acid-sensing ion channels 42 , and the voltage-gated potassium channel, Kv1.2 43 .…”

A loosely coordinated interaction site for arachidonic acid on ASICs

“…However, mutagenesis may alter channel function and eliminate the AA effect for a number of unintended reasons, so a clearer picture of how lipids interact with this family of channels has been critically lacking. In the present issue of JGP , Ananchenko and Musgaard (2023) have provided the first atomistic look of lipid interaction with ASICs using molecular dynamics simulations, a critical first step in understanding lipids as a potential regulator of this class of channels.…”

“…The work by Ananchenko and Musgaard (2023) takes the first important step toward filling in this gap in our understanding. They used the MARTINI forcefield and coarse-grained molecular dynamics simulations to examine the binding of AA to the transmembrane segments of human ASIC1a and ASIC3.…”