Differentiation of Boc-N-protected a/b-hybrid peptides containing b-Caa-L-Ala-b-Caa-OMe and b-Caa-L-Ala-bCaa-NHMe at the C-terminus by electrospray ionization tandem mass spectrometryOver the past few years, there has been growing interest in peptides derived from non-natural amino acids because of their importance in pharmaceutical and foldamer chemistry. [1][2][3] Such efforts have invariably been to understand their conformational behavior and develop them into biomolecules with novel properties. The b-peptides, a very important class in the foldamer domain, derived from b-amino acids, exhibited several novel secondary structures.[4] The fundamental structural element in proteins is the b-strand, which is known to be conformationally suitable for specific recognition by bimolecular receptors such as proteolytic enzymes, major histocompatibility complex (MHC) proteins and transferases. [5][6][7] A 12/10-mixed helix unique to the b-peptides was discovered -Caa) with alternating chirality at the Cb carbon.[5] It was also shown in their studies on peptides with alternating b-Caa and b-h-Gly, the formation of right-as well as lefthanded 10/12-and 12/10-helices.[6] They also demonstrated that the a/b-hybrid peptides containing alternating L-Ala and b-Caa, with the L-Ala-b-Caa-L-Ala (a-b-a) sequence at the C-terminus, formed very robust 11/9 mixed helices [9] and the a/b-hybrid peptides with the b-Caa-L-Ala-b-Caa (b-a-b) sequence at the C-terminus formed an unusual and novel three residue (b-a-b) turn at the C-terminus, nucleated by an 11/9 helix at the N-terminus, thus resulting in a rather well-defined helix-turn (HT) motif in these peptides. [10] Mass spectral characterization of a-amino acid peptides is well documented in the literature. [11][12][13] The tandem mass spectrometry (MS/MS) of protonated peptides [14][15][16] formed in electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) [17] has been an established tool in determining amino acid sequence of peptides. There are