Helix macrodipole control of β3-peptide 14-helix stability in water

β-Peptides have attracted considerable attention by virtue of their ability to populate helical secondary structures in methanol, even in the absence of stabilizing tertiary interactions. Recent efforts in β-peptide design have produced few β3-peptides that form stable 14-helices in water; those that do require stabilizing intramolecular salt bridges on two of three helical faces and therefore possess limited utility as tools in biological research. Here we show that favorable interactions with the 14-helix macrodipole significantly stabilize the 14-helix in water, alleviating the need for multiple salt bridges on two of three helical faces. We also report the previously unrecognized stabilization of 14-helix structure by γ-branched β3-amino acids. The most structured molecules we describe are highly heterogeneous at the primary sequence level, containing seven different β3-amino acids within an 11-residue sequence. These results represent the essential first step toward the design of well-folded 14-helices that explore the interactions between β3-peptides and biological macromolecules in vitro and in vivo. Copyright © 2003 American Chemical Society.