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Open AccessArticle

Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels

Schrödinger, Inc. 120 W. 45th St, New York, NY 10036, USA
PhD Program in Biological and Biomedical Sciences, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, USA
Author to whom correspondence should be addressed.
Toxins 2020, 12(10), 652;
Received: 22 July 2020 / Revised: 21 September 2020 / Accepted: 9 October 2020 / Published: 12 October 2020
(This article belongs to the Section Animal Venoms)
Peptide toxins isolated from venomous creatures, long prized as research tools due to their innate potency for ion channels, are emerging as drugs as well. However, it remains challenging to understand why peptide toxins bind with high potency to ion channels, to identify residues that are key for activity, and to improve their affinities via mutagenesis. We use WaterMap, a molecular dynamics simulation-based method, to gain computational insight into these three questions by calculating the locations and thermodynamic properties of water molecules in the peptide toxin binding sites of five ion channels. These include an acid-sensing ion channel, voltage-gated potassium channel, sodium channel in activated and deactivated states, transient-receptor potential channel, and a nicotinic receptor whose structures were recently determined by crystallography and cryo-electron microscopy (cryo-EM). All channels had water sites in the peptide toxin binding site, and an average of 75% of these sites were stable (low-energy), and 25% were unstable (medium or high energy). For the sodium channel, more unstable water sites were present in the deactivated state structure than the activated. Additionally, for each channel, unstable water sites coincided with the positions of peptide toxin residues that previous mutagenesis experiments had shown were important for activity. Finally, for the sodium channel in the deactivated state, unstable water sites were present in the peptide toxin binding pocket but did not overlap with the peptide toxin, suggesting that future experimental efforts could focus on targeting these sites to optimize potency. View Full-Text
Keywords: peptide toxin; ion channel; WaterMap; cryo-EM; drug discovery peptide toxin; ion channel; WaterMap; cryo-EM; drug discovery
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MDPI and ACS Style

Shah, B.; Sindhikara, D.; Borrelli, K.; Leffler, A.E. Water Thermodynamics of Peptide Toxin Binding Sites on Ion Channels. Toxins 2020, 12, 652.

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