Factors governing 3₁₀‐helix vs α‐helix formation in peptides: Percentage of C^α‐tetrasubstituted α‐amino acid residues and sequence dependence

Abstract

As an additional step toward the dissection of the factors responsible for the onset of 3(10)-helix vs alpha-helix in peptides, in this paper we describe the results of a three-dimensional (3D) structural analysis by x-ray diffraction of the N(alpha)-acylated heptapeptide alkylamide mBrBz-L-Iva-L-(alphaMe)Val-L-Abu-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe characterized by a single (L-Abu3) C(alpha)-trisubstituted and six C(alpha)-tetrasubstituted alpha-amino acids. We find that in the crystal state this peptide is folded in a mixed helical structure with short elements of 3(10)-helix at either terminus and a central region of alpha-helix. This finding, taken together with the published NMR and x-ray diffraction data on the all C(alpha)-methylated parent sequence and its L-Val2 analog (also the latter heptapeptide has a single C(alpha)-trisubstituted alpha-amino acid) strongly supports the view that one C(alpha)-trisubstituted alpha-amino acid inserted near the N-terminus of an N(alpha)-acylated heptapeptide alkylamide sequence may be enough to switch a regular 3(10)-helix into an essentially alpha-helical conformation. As a corollary of this work, the x-ray diffraction structure of the N(alpha)-protected, C-terminal tetrapeptide alkylamide Z-L-(alphaMe)Val-L-(alphaMe)Phe-L-(alphaMe)Val-L-Iva-NHMe, also reported here, is clearly indicative of the preference of this fully C(alpha)-methylated, short peptide for the 3(10)-helix. As the same terminally blocked sequence is mixed 3(10)/alpha-helical in the L-Abu3 heptapeptide amide but regular 3(10)-helical in the tetrapeptide amide and in the parent heptapeptide amide, these results point to an evident plasticity even of a fully C(alpha)-methylated short peptide.

Spectroscopic Evidence for the Formation of Helical Structures in Gas-Phase Short Peptide Chains

“…This gas-phase helical folding ( Figure 8) can be considered as the isolated counterpart of structures encountered in crystals of model Aib-based peptides. [39][40][41][42] Beyond this assignment, the present work, in particular the synthesized IR spectra, illustrates the diversity of spectral IR signatures among the several conformations expected a priori, a Observed in the R2PI spectra of capped di-and tripeptides b Low-frequency modes (<50 cm -1 ) were calculated at the B3LYP/6-31+G(d) level of theory for selected conformations and are given in reciprocal centimeters. A rough description of the calculated modes is given, in particular the motion of the phenyl ring relative to the backbone, expected to be crucial for the FC activity.…”

Secondary Structure, a Missing Component of Sequence-Based Minimotif Definitions

“…One explanation is that different minimotif targets select a specific structure from an ensemble of multiple structures. The formation of such secondary structures seems to be highly dependent on amino acid substitutions where even single point mutations alter secondary structures [90], [100].…”

De novo design, synthesis and solution conformational study of two didehydroundecapeptides: effect of nature and number of amino acids interspersed between Phe residues

“…In peptides containing Aib residues, a 3 10 ‐helix is preferred for shorter peptides ( n ~ 8 or less) and an α ‐helix for longer peptides ( n = 9–20) . Factors governing the type of helical structure (3 10 vs α ), namely, main chain length, sequence dependence (Aib content), inherent relative stabilities of the two helices, the additional intramolecular C=O … H–N hydrogen bond in a 3 10 ‐helix for the same number of residues, environmental factors like solvent polarity and temperature, helix macro dipoles, have been investigated and discussed . Molecular dynamics simulations and free energy calculations suggest that energetically the two helical forms are very close .…”