Covalent side chain cross-linking is a widely utilized strategy to control folding in short peptides. We have begun to develop and apply cross-linking reactions that are bioorthogonal and dynamically reversible in water for this purpose. The use of such cross-linking chemistries opens several interesting possibilities, including the creation of a dynamic mixture of cross-linked species from an unprotected peptide in solution or the stabilization of a bioactive conformation even if that conformation is not previously known. Towards these ends, we have examined the folding behavior of a variety of peptides bearing aminooxy and vicinal amino alcohol side chains. Upon treatment with a mild oxidant in aqueous solution, these residues form oxime-based side chain cross-links that can increase the helical content of short, partially helical sequences or stabilize a protein-protein complex involving helical secondary structure. In the protein-protein complex, data are presented that show the reported method can be used to select a single cross-link that best promotes the bound state out of many possible cross-linked forms.

Bioorthogonal and dynamically reversible cross-linking strategies to promote peptide folding and stabilize protein-protein complexes

246th National Meeting (2013)

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