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J Am Chem Soc. 2009 Mar 11;131(9):3377-84. doi: 10.1021/ja809580b.

Metal-binding dependent disruption of membranes by designed helices.

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Department of Biochemistry and Biophysics, and the Department of Chemistry, University of Pennsylvania, Stellar-Chance Building Room 1010, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.


The de novo design of molecular switching peptides is of increasing interest because it tests and extends our fundamental understanding of this process while laying the groundwork for the creation of new chemical and biological sensors. Here, an alpha-helical amphiphilic cell-lytic peptide, mastoparan X, was engineered to bind divalent cations. Binding of Zn(II) or Ni(II) to the designed peptide Mst-HH stabilizes the lytic amphiphilic structure and increases the activity of the peptide. Although both Zn(II) and Ni(II) activate Mst-HH for membrane lysis, they appear to do so via different mechanisms. Additionally, a series of metal binding-site mutants were synthesized to assess the relationship of charge and helical propensity to the toxicity and switchability. Additionally, by changing the characteristics of the metal-binding ligands, we can vary the selectivity of the site.

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