Preferred solution conformation of peptides rich in the lipophilic, chiral, Cα-methylated α-amino acid (αMe)Aoc

Abstract

The lipophilic, chiral, C(alpha)-methylated alpha-amino acid L-(alphaMe)Aoc (2-methyl-2-amino-octanoic acid) was prepared using a chemo-enzymatic approach. Two series of terminally protected model peptides, from dimer through to hexamer, containing L-(alphaMe)Aoc in combination with either Gly or Aib, were synthesized by solution methods and were fully characterized. A solution conformational analysis, based on FT-IR absorption, 1H-NMR and circular dichroism (CD) techniques, was performed with the aim at determining the preferred conformation of this novel amino acid and the relationship between chirality at its alpha-carbon atom and screw sense of the helix that is formed. The results obtained strongly support the view that L-(alphaMe)Aoc favours the formation of the right-handed 3(10)-helical conformation.

(αMe)Nva: stereoselective syntheses and preferred conformations of selected model peptides

“…The above‐mentioned preferences of the (αMe)Nva peptides, together with the strictly comparable properties of the peptides rich in the Aib (4–7,9), Iva (12,13,16) (αMe)Aoc (14) and (αMe)Aun (15) residues, reinforce the conclusion that amino acids with a C α ‐methyl group and a C α ‐linear alkyl group strongly bias their peptides into a folded/helical structure. It is worth noting that this finding represents an additional manifestation of the Thorpe–Ingold or gem ‐dialkyl effect (55).…”

“…The work reported here features (αMe)Nva with a n ‐propyl side‐chain, intermediate in length between the shorter side‐chains of Aib (methyl) (4–7,9) and Iva (ethyl) (12,13,16), and the much longer, highly lipophilic side‐chains of (αMe)Aoc ( n ‐hexyl) (14) and (αMe)Aun ( n ‐nonyl) (15). More specifically, we prepared a set of selected, model l (or S)‐(αMe)Nva peptides to the pentamer level either using the optically pure l ‐enantiomer obtained from a stereoselective chemical or a chemoenzymatic synthesis, or by side‐chain hydrogenation of the corresponding l ‐Mag peptides (17).…”

“…In this connection, inter alia we investigated the fundamental aspects of these effects for a number of chiral, C α ‐methylated α‐amino acids (8) and compared them with some other analogs, notably Aib, the achiral prototypical residue of this family (4–7,9). In recent years, study of the conformational preferences of C α ‐methylated α‐amino acids with a linear, saturated aliphatic side‐chain of widely diverging length has particularly attracted our attention (12–15).…”

“…In the peptides examined, the (αMe)Nva and Nva residues are combined with l ‐Ala and/or Aib. The major target of this research was to determine the conformational preferences of (αMe)Nva and to correlate them to those of the other C α ‐methylated α‐amino acids with a ‐(CH 2 ) n ‐CH 3 side‐chain studied previously (12–16). Furthermore, we decided to investigate the role of: (i) C α ‐methylation on peptide turn and helix induction, and (ii) (αMe)Nva C α ‐chirality on helical screw sense.…”