A potent and selective peptide blocker of the Kv1.3 channel: Prediction from free-energy simulations and experimental confirmation

Rashid, M, Heinzelmann, G, Huq, R, Tajhya, R, Chang, S, Chhabra, S, Pennington, M, Beeton, C, Norton, R and Kuyucak, S 2013, 'A potent and selective peptide blocker of the Kv1.3 channel: Prediction from free-energy simulations and experimental confirmation', PLoS ONE, vol. 8, no. 11, e78712, pp. 1-10.


Document type: Journal Article
Collection: Journal Articles

Title A potent and selective peptide blocker of the Kv1.3 channel: Prediction from free-energy simulations and experimental confirmation
Author(s) Rashid, M
Heinzelmann, G
Huq, R
Tajhya, R
Chang, S
Chhabra, S
Pennington, M
Beeton, C
Norton, R
Kuyucak, S
Year 2013
Journal name PLoS ONE
Volume number 8
Issue number 11
Article Number e78712
Start page 1
End page 10
Total pages 10
Publisher Public Library of Science
Abstract The voltage-gated potassium channel Kv1.3 is a well-established target for treatment of autoimmune diseases. ShK peptide from a sea anemone is one of the most potent blockers of Kv1.3 but its application as a therapeutic agent for autoimmune diseases is limited by its lack of selectivity against other Kv channels, in particular Kv1.1. Accurate models of Kv1.x-ShK complexes suggest that specific charge mutations on ShK could considerably enhance its specificity for Kv1.3. Here we evaluate the K18A mutation on ShK, and calculate the change in binding free energy associated with this mutation using the path-independent free energy perturbation and thermodynamic integration methods, with a novel implementation that avoids convergence problems. To check the accuracy of the results, the binding free energy differences were also determined from path-dependent potential of mean force calculations. The two methods yield consistent results for the K18A mutation in ShK and predict a 2 kcal/mol gain in Kv1.3/Kv1.1 selectivity free energy relative to wild-type peptide. Functional assays confirm the predicted selectivity gain for ShK[K18A] and suggest that it will be a valuable lead in the development of therapeutics for autoimmune diseases. © 2013 Rashid et al.
Subject Biomolecular Modelling and Design
Keyword(s) potassium channel blocking agent
potassium channel Kv1.1
potassium channel Kv1.3
ShK peptide
unclassified drug
sea-anemone toxin
memory t-cells
autoimmune-diseases
shk toxin
molecular-dynamics
potassium channels
multiple-sclerosis
k+ channels
protein
lymphocytes
DOI - identifier 10.1371/journal.pone.0078712
Copyright notice Copyright © 2013 Rashid et al. This is an open-access article distributed under the terms of the Creative Commons
ISSN 1932-6203
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