Covalent capture and stabilization of cylindrical β-sheet peptide assemblies

Abstract

The utility of noncovalent approaches to molecular self-assembly is often limited by kinetic instability of the resulting constructs. In an effort to surmount this difficulty, we have employed noncovalent interactions between self-assembling cyclic peptide subunits to direct covalent bond formation, resulting in cylindrical β-sheet dimers that are both kinetically and thermodynamically stable. In the two peptide systems examined, we found that intersubunit hydrogen bonding serves important but distinct functions. For olefin metathesis of homoallylglycine (Hag)-bearing peptide 1, hydrogen bonding drives the reaction by increasing olefin effective molarity. In contrast, for disulfide isomerization of monomeric cystine peptide 5-SS, hydrogen bonding appears to control partitioning between two alternative disulfide-bonded dimers by contributing to the stability of the hydrogen-bonded isomer. Our proposed mechanism for the latter transformation is reminiscent both of thiolcatalyzed unscrambling of RNase A and oxidative refolding pathways of natural proteins and protein fragments.