Abstract
Assignment of the most established electronic circular dichroism (ECD) spectra of polypeptides and foldamers is either “evidence based” or relies on the 3D structures of longer oligomers of limited internal dynamics, which are derived from NMR spectroscopy (or X‐ray) data. Critics warn that the use of NMR spectroscopy and ECD side by side has severe limitations for flexible molecules because explicit knowledge of conformational ensembles is a challenge. Herein, an old–new method of comparing ab initio computed and measured vibrational circular dichroism (VCD) data is presented to validate both the structures (conf(i)) and their relative weights (c(i)) that make up the conformational ensemble. Based on the array of {conf(i), c(i)}, the pure ECD spectra, g(i)conf(i), can be ab initio calculated. The reconstructed spectrum Σc(i)g(i)conf(i) can thus help to assign any experimental ECD counterparts. Herein, such a protocol is successfully applied to flexible foldamer building blocks of sugar β‐amino acid diamides. The epimeric pair of the model system was selected because these molecules were conformationally tunable by simple chemical modification, and thus, the robustness of the current approach could be probed. The initial hydrogen bond (NH⋅⋅⋅O) eliminated by N‐methylation reorients the amide plain, which influences the chiroptical properties of the foldamer building block; this structural change is successfully monitored by changes to the VCD and ECD transitions, which are now assigned to pure conformers. The current method seems to be general and effective without requiring extensive CPU and spectroscopic resources.
Highlights
Both proteinogenic a- and non-natural, but biocompatible, b, g, d, and e-amino acids are used as Lego-like building blocks to modify and redesign proteins, chimera peptides, and foldamers.[1,2] To be able to tailor the structure and properties of these macromolecules, a firm understanding of the conformational properties of the building blocks themselves is required; the structural elucidation of such molecules is a hot topic of current structural chemistry and biology
The groups of Seebach and Gellman both published further examples, which illustrated that an NMR spectroscopy–electronic circular dichroism (ECD) contradiction did exists for hybrid foldamers, for systems composed of a- and b- or a- and gamino acid residues.[2,19]
We propose to complete ECD assignment through cross-validated vibrational circular dichroism (VCD) information, in combination with a structural ensemble derived from molecular mechanics (MM) and ab initio structure ensemble data and spectra
Summary
Www.chemeurj.org dilute solutions are directly attributed to structural information derived from 5–10 times more concentrated solution-state data or from structural information determined by solid-state characterization; this raised numerous concerns.[2,15,16,17] For example, Glättli et al noted that, for H-(b-HVal-b-HAla-b-HLeu) and its dimethylated form (H-[b-HVal(Me2)-b-HAla(Me2)-b-HLeu(Me2)]2), which presented nearly identical ECD spectra, the NMR spectroscopy based structural assignment of a 314-helix was unlikely to be correct because the dimethylated variant could not form such a conformer due to steric repulsion.[15,18] In addition, the groups of Seebach and Gellman both published further examples, which illustrated that an NMR spectroscopy–ECD contradiction did exists for hybrid foldamers, for systems composed of a- and b- or a- and gamino acid residues.[2,19] The problem with the concept of using NMR spectroscopy as the high-resolution referencing method for ECD arises from the fact that, for short and flexible oligomers, the available J-coupling constants, NOE, and/or secondary chemical shift information is just too sparse for reconstructing ensembles of multiple backbone conformers. ECD spectroscopy, which is sensitive to small structural variations of the amide planes that are undetectable by NMR spectroscopy, is ideal for complementing or replacing these methodologies.[16,17]
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