Free energy analysis of conductivity and charge selectivity of M2GlyR-derived synthetic channels

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dc.contributor.author Chen, Jianhan
dc.contributor.author Tomich, John M.
dc.date.accessioned 2014-10-14T19:04:54Z
dc.date.available 2014-10-14T19:04:54Z
dc.date.issued 2014-10-14
dc.identifier.uri http://hdl.handle.net/2097/18367
dc.description.abstract Significant progresses have been made in the design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the second transmembrane domain of the α-subunit of the glycine receptor (GlyR). The latest designs, including p22 (KKKKP ARVGL GITTV LTMTT QS), are highly soluble in water with minimal aggregation propensity and insert efficiently into cell membranes to form highly conductive ion channels. The last obstacle to a potential lead sequence for channel replacement treatment of CF patients is achieving adequate chloride selectivity. We have performed free energy simulation to analyze the conductance and charge selectivity of M2GlyR-derived synthetic channels. The results reveal that the pentameric p22 pore is non-selective. Moderate barriers for permeation of both K+ and Cl- are dominated by the desolvation cost. Despite previous evidence suggesting a potential role of threonine side chains in anion selectivity, the hydroxyl group is not a good surrogate of water for coordinating these ions. We have also tested initial ideas of introducing additional rings of positive changes to various positions along the pore to increase anion selectivity. The results support the feasibility of achieving anion selectivity by modifying the electrostatic properties of the pore, but at the same time suggest that the peptide assembly and pore topology may also be dramatically modified, which could abolish the effects of modified electrostatics on anion selectivity. This was confirmed by subsequent two-electrode voltage clamp measurements showing that none of the tested mono-, di- and tri-Dap substituted sequences was selective. The current study thus highlights the importance of controlling channel topology besides modifying pore electrostatics for achieving anion selectivity. Several strategies are now being explored in our continued efforts to design an anion selective peptide channel with suitable biophysical, physiological and pharmacological properties as a potential treatment modality for channel replacement therapy. en_US
dc.language.iso en_US en_US
dc.relation.uri http://www.sciencedirect.com/science/article/pii/S0005273614000807 en_US
dc.subject Cystic fibrosis en_US
dc.subject Molecular dynamics en_US
dc.subject Potential of mean force en_US
dc.subject Anion selectivity en_US
dc.subject Ion channels en_US
dc.subject Peptide design en_US
dc.title Free energy analysis of conductivity and charge selectivity of M2GlyR-derived synthetic channels en_US
dc.type Article (author version) en_US
dc.date.published 2014 en_US
dc.citation.doi 10.1016/j.bbamem.2014.02.016 en_US
dc.citation.epage 2325 en_US
dc.citation.issue 9 en_US
dc.citation.jtitle Biochimica et Biophysica Acta – Biomembranes en_US
dc.citation.spage 2319 en_US
dc.citation.volume 1838 en_US
dc.contributor.authoreid jianhanc en_US
dc.contributor.authoreid jtomich en_US


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