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Is Lipid Bilayer Binding a Common Property of Inhibitor Cysteine Knot Ion-Channel Blockers?

Yevgen O. Posokhov ^*, Philip A. Gottlieb , Michael J. Morales , Frederick Sachs  and Alexey S. Ladokhin ^*

^* Department of Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, Kansas 66160; and Department of Physiology and Biophysics, State University of New York, Buffalo, New York 14214

Correspondence: Address reprint requests and inquiries to Alexey S. Ladokhin, E-mail: aladokhin{at}kumc.edu.

Recent studies of several ICK ion-channel blockers suggest that lipid bilayer interactions play a prominent role in their actions. Structural similarities led to the hypothesis that bilayer interactions are important for the entire ICK family. We have tested this hypothesis by performing direct measurements of the free energy of bilayer partitioning (G) of several peptide blockers using our novel quenching-enhanced fluorescence titration protocol. We show that various ICK peptides demonstrate markedly different modes of interaction with large unilamellar lipid vesicles. The mechanosensitive channel blocker, GsMTx4, and its active diastereomeric analog, D-GsMTx4, bind strongly to both anionic and zwitterionic membranes. One potassium channel gating modifier, rHpTx2gs, interacts negligibly with both types of vesicles at physiological pH, whereas another, SGTx1, interacts only with anionic lipids. The slope of G dependence on surface potential is very shallow for both GsMTx4 and D-GsMTx4, indicating complex interplay of their hydrophobic and electrostatic interactions with lipid. In contrast, a cell-volume regulator, GsMTx1, and SGTx1 exhibit a very steep G dependence on surface potential, resulting in a strong binding only for membranes rich in anionic lipids. The high variability of 5 kcal/mole in observed G shows that bilayer partitioning is not a universal property of the ICK peptides interacting with ion channels.

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