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Open AccessArticle

Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations

1
Department of Neurosurgery, Mayo Clinic Health System-Franciscan Healthcare in La Crosse, La Crosse, WI 54601, USA
2
Department of Biomedical Sciences, Creighton University, Omaha, NE 68178, USA
3
Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(6), 1261; https://doi.org/10.3390/ijms20061261
Received: 6 March 2019 / Accepted: 10 March 2019 / Published: 13 March 2019
Chlorotoxin (CTX) is a 36–amino acid peptide with eight Cys residues that forms four disulfide bonds. It has high affinity for the glioma-specific chloride channel and matrix metalloprotease-2. Structural and binding properties of CTX analogs with various Cys residue substitutions with l-α-aminobutyric acid (Abu) have been previously reported. Using 4.2 µs molecular dynamics, we compared the conformational and essential space sampling of CTX and analogs with selective substitution of the Cys residues and associated disulfide bonds with either Abu or Ser. The native and substituted peptides maintained a high degree of α-helix propensity from residues 8 through 21, with the exception of substitution of the Cys5–Cys28 residues with Ser and the Cys16–Cys33 residues with Abu. In agreement with previous circular dichroism spectropolarimetry results, the C-terminal β-sheet content varied less from residues 25 through 29 and 32 through 36 and was well conserved in most analogs. The Cys16–Cys33 and Cys20–Cys35 disulfide-bonded residues appear to be required to maintain the αβ motif of CTX. Selective substitution with the hydrophilic Ser, may mitigate the destabilizing effect of Cys16–Cys33 substitution through the formation of an inter residue H-bond from Ser16:OγH to Ser33:OγH bridged by a water molecule. All peptides shared considerable sampled conformational space, which explains the retained receptor binding of the non-native analogs. View Full-Text
Keywords: αβ motif; Abu; chlorotoxin; Cys; disulfide bond; insectotoxin; isosteric substitution; l-α-aminobutyric acid; molecular dynamics; Ser αβ motif; Abu; chlorotoxin; Cys; disulfide bond; insectotoxin; isosteric substitution; l-α-aminobutyric acid; molecular dynamics; Ser
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MDPI and ACS Style

Gregory, A.J.; Voit-Ostricki, L.; Lovas, S.; Watts, C.R. Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations. Int. J. Mol. Sci. 2019, 20, 1261. https://doi.org/10.3390/ijms20061261

AMA Style

Gregory AJ, Voit-Ostricki L, Lovas S, Watts CR. Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations. International Journal of Molecular Sciences. 2019; 20(6):1261. https://doi.org/10.3390/ijms20061261

Chicago/Turabian Style

Gregory, Andrew J.; Voit-Ostricki, Leah; Lovas, Sándor; Watts, Charles R. 2019. "Effects of Selective Substitution of Cysteine Residues on the Conformational Properties of Chlorotoxin Explored by Molecular Dynamics Simulations" Int. J. Mol. Sci. 20, no. 6: 1261. https://doi.org/10.3390/ijms20061261

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