alexa The use of ion mobility mass spectrometry to assist protein design: a case study on zinc finger fold versus coiled coil interactions.
Pharmaceutical Sciences

Pharmaceutical Sciences

Pharmaceutica Analytica Acta

Author(s): Berezovskaya Y, Porrini M, Nortcliffe C, Barran PE

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Abstract The dramatic conformational change in zinc fingers on binding metal ions for DNA recognition makes their structure-function behaviour an attractive target to mimic in de novo designed peptides. Mass spectrometry, with its high throughput and low sample consumption provides insight into how primary amino acid sequence can encode stable tertiary fold. We present here the use of ion mobility mass spectrometry (IM-MS) coupled with molecular dynamics (MD) simulations as a rapid analytical platform to inform de novo design efforts for peptide-metal and peptide-peptide interactions. A dual peptide-based synthetic system, ZiCop based on a zinc finger peptide motif, and a coiled coil partner peptide Pp, have been investigated. Titration mass spectrometry determines the relative binding affinities of different divalent metal ions as Zn(2+) > Co(2+) ≫ Ca(2+). With collision induced dissociation (CID), we probe complex stability, and establish that peptide-metal interactions are stronger and more 'specific' than those of peptide-peptide complexes, and the anticipated hetero-dimeric complex is more stable than the two homo-dimers. Collision cross-sections (CCS) measurements by IM-MS reveal increased stability with respect to unfolding of the metal-bound peptide over its apo-form, and further, larger collision cross sections for the hetero-dimeric forms suggest that dimeric species formed in the absence of metal are coiled coil like. MD supports these structural assignments, backed up by data from visible light absorbance measurements. This article was published in Analyst and referenced in Pharmaceutica Analytica Acta

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