Laser Spectroscopy of Conformationally Constrained α/β-Peptides: Ac-ACPC-Phe-NHMe and Ac-Phe-ACPC-NHMe

Abstract

Single-conformation ultraviolet and infrared spectra have been recorded under the isolated molecule conditions of a supersonic expansion for three conformationally constrained alpha/beta-peptides, Ac-L-Phe-ACPC-NHMe (alpha(L)beta(ACPC)), Ac-ACPC-L-Phe-NHMe (beta(ACPC)alpha(L)), and Ac-ACPC-D-Phe-NHMe (beta(ACPC)alpha(D)). These three molecules are close analogues of the hAla-containing alpha/beta-peptide counterparts Ac-L-Phe-beta(3)-hAla-NHMe, Ac-beta(3)-hAla-L-Phe-NHMe, and Ac-beta(3)-hAla-D-Phe-NHMe, which have been studied recently by James et al. (J. Am. Chem. Soc. 2009, 131, 6574). Incorporation of the beta-amino acid trans-2-aminocyclopentanecarboxylic acid (ACPC) constrains the beta-peptide backbone via the cyclopentane ring, producing clear changes in the conformational preferences relative to the unconstrained analogues. The conformational control is manifested most obviously in the complete absence of C6 H-bonded rings, which were dominant in the unconstrained alpha/beta-peptides. The most stable C6 ring structure (C6a) in the absence of the ACPC ring cannot be formed in its presence, while a secondary C6 ring (C6b) has its energy destabilized by approximately 20 kJ/mol. In alpha(L)beta(ACPC), the preference for C5 structures in the N-terminal position, combined with the strong preference for C8 structures in the beta-peptide subunit, leads to the observation of two C5/C8 bifurcated double ring conformers. Both C8/C7 sequential double rings and C11 single rings are observed in beta(ACPC)alpha(L) and beta(ACPC)alpha(D). Here, the ACPC ring selectively stabilizes the C8a ring over other possible C8 structures. Finally, the combined evidence from IR and UV spectra lead to tentative assignments for diastereomeric pairs, exhibiting small but understandable shifts in the IR and UV spectra induced by the change in chirality at the alpha-peptide chiral center.

How Cations Change Peptide Structure

“…Such investigations of isolated peptides in the gas phase offer an unbiased view of structure-formation trends intrinsic to the molecule, a strategy that is successful for charged and uncharged amino acids and peptides. [20][21][22][23][24][25][26][27][28][29][30] By the stepwise addition of perturbing contributions, in this case, the presence of cations, we aim to determine the main contributions to protein secondary structure formation in a bottom-up approach. The success of such an approach is critically linked to the quality of the description of the potential-energy surface of the system under investigation.…”

“…Previous studies have shown similar behavior owing to conformational ensembles for peptides in the gas phase at finite temperature. [22][23][24][25][26][27] Furthermore, the energy differences of the low free-energy conformers lie within the uncertainty of the employed method, as discussed in the section called Benchmarks below. Consequently, an ensemble of conformations is assumed.…”

Isolated Neutral Peptides

“…Vibrational couplings make the interpretation less easy, and confident assignments rely on a large spectral range (the whole amide I-III regions), especially when spectral resolution is limited, usually 1% of the IR frequency for a freeelectron source [48,54,55,66,69,79,80,82,83,95,97,105,108,131,132,136,141,142]. Difference frequency generation from table-top OPOs [52,64,90,104,120,126,127,137,139,144,145] has become a valuable alternative source to FELs, providing spectral resolutions in the cm À1 range, and solid conformational assignments have emerged from studies combining amide I/II and amide A spectral ranges (Fig. 1b).…”

“…In addition, the folding from the NH of the second Ala residue into a C7 H-bond is hampered by significant entropic effects which favour extended forms because of their multiple low frequency modes. Amidated models, [63,70,73,83,114] as well as di-or tri-peptides with Phe or Trp as first residue [84,85,94,104,112], have also revealed C5-containing secondary structures. In these conformations, the C5 H-bond occurring at the aromatic residue is additionally stabilised by an interaction between the π system of the aromatic ring and the NH of the following residue along the chain , making the 5-π motif very common among these secondary structures.…”

“…More recently, other peptides, with longer spacers between amide bonds, i.e. β-and γ-peptides, having respectively two or three methylene spacers between their peptide bonds, have been investigated, either alone or in combination between them or with alpha peptides [52,104,122,123,[125][126][127][128][143][144][145]. More flexible C11, C8 and C6 H-bonded structures in β-peptides as compared to their C10, C7 and C5 equivalents in the regular α-peptide are a general characteristic of these species.…”