Consecutive Cyclic Pentapeptide Modules Form Short alpha-Helices that are Very Stable to Water and Denaturants

摘要

The alpha-helix accounts for approximately 30% of protein structures.Often only a few alpha-helical turns of exposed protein surfaces are recognized by other proteins,DNA,or RNA.Such helical segments in isolation could be valuable biological probes and drug leads,however,the corresponding short peptides (<15 residues) do not form thermodynamically stable alpha-helices in water.Helicity can be stabilized to some extent in longer peptides by using helix-nucleating templates,metal-ion clips,unnatural amino acids,or noncovalent and covalent side chain constraints (disul-fide,hydrazone,lactam,aliphatic.Small molecules that stabilize or mimic an alpha-turn have proven elusive,although alpha-helix side chains have been mounted on non-peptidic scaffolds.Here we describe a promising modular strategy for mimicking short a-helices by using consecutive sequences of cyclic pentapeptide modules to form short alpha-helices that are remarkably stable in water,resistant to protein denaturants,likely tolerant of amino acid substitution,easy to synthesize,and with promising utility for biological applications.