2021
DOI: 10.1101/2021.03.12.435097
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Markov State Models of Proton- and Gate-Dependent Activation in a Pentameric Ligand-Gated Ion Channel

Abstract: Ligand-gated ion channels conduct currents in response to chemical stimuli, mediating electrochemical signaling in neurons and other excitable cells. For many channels the mechanistic details of gating remain unclear, partly due to limited structural data and simulation timescales. Here, we used enhanced sampling to simulate the pH-gated channel GLIC, and construct Markov state models (MSMs) of gating transitions. Consistent with new functional recordings reported here in oocytes, our analysis revealed differe… Show more

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Cited by 3 publications
(3 citation statements)
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“…Due in part to low conductance, and technical challenges to measuring robust single-channel currents under highly acidic conditions, efforts by multiple groups have yet to establish the maximal open probability for GLIC by electrophysiology ( 8 , 52 ). However, we recently calculated an open probability of only 17% for GLIC at low pH, based on Markov state modeling of enhanced-sampling MD simulations ( 53 Preprint ). Interestingly, low-pH crystallization of GLIC in lipidic mesophases also produced a closed structure, and a C-terminally tagged variant exhibited partial occupancy of both open and locally closed conformations in the same crystal form ( 32 , 54 ): thus, even X-ray studies indicate a propensity for partial closure at low pH, and a role for crystal packing in influencing conformational selection.…”
Section: Discussionmentioning
confidence: 99%
“…Due in part to low conductance, and technical challenges to measuring robust single-channel currents under highly acidic conditions, efforts by multiple groups have yet to establish the maximal open probability for GLIC by electrophysiology ( 8 , 52 ). However, we recently calculated an open probability of only 17% for GLIC at low pH, based on Markov state modeling of enhanced-sampling MD simulations ( 53 Preprint ). Interestingly, low-pH crystallization of GLIC in lipidic mesophases also produced a closed structure, and a C-terminally tagged variant exhibited partial occupancy of both open and locally closed conformations in the same crystal form ( 32 , 54 ): thus, even X-ray studies indicate a propensity for partial closure at low pH, and a role for crystal packing in influencing conformational selection.…”
Section: Discussionmentioning
confidence: 99%
“…However, there is precedence in this family for flickering between states even at high agonist concentrations [32,33] and for open probabilities well below 100% at activating conditions [34,35,36,37]. In recent computational work, we estimated the low-pH open probability of GLIC to 17% using Markov state modeling [38] -notably similar to the tolerated contribution (18%) of the open structure in our linear-combination fits, Supplementary Figure S1. There are thus several indications the SANS curve under activating conditions might be due to an average of mixed states, mostly closed, but some similar to open crystal structures.…”
Section: Discussionmentioning
confidence: 55%
“…However, there is precedence in this family for flickering between states even at high agonist concentrations ( 36 , 37 ) and for open probabilities well below 100% at activating conditions ( 38 41 ). In recent computational work, we estimated the low-pH open probability of GLIC to 17% using Markov state modeling ( 42 )—notably similar to the tolerated contribution (18%) of the open structure in our linear-combination fits ( SI Appendix , Fig. S1 and Table S2 ).…”
Section: Discussionmentioning
confidence: 81%