Applying γ-Substituted Prolines in the Foldon Peptide: Polarity Contradicts Preorganization

Rational choice of chemical modifications to proline residues allows the preorganization principle to be exploited for more stable assembly of the foldon domain as a tag for trimerization. With systematic knowledge of how chemical and steric variations of the ring substituents affect the relative stabilities of exo and endo puckers, the preorganization principle should then be usable in biotechnologically synthesized foldon mutants and applicable for protein tagging elsewhere. Tailoring the properties of the­ foldon­ structure: γ‐Substituted proline units were successfully applied to the engineering of the foldon trimerization tag. The initial structure was found to be largely unaltered but the melting temperatures were found to be substantially affected, allowing both stabilization and destabilization of the native fold.