Theoretical Study of the Raman Optical Activity Spectra of 3₁₀‐Helical Polypeptides

Abstract

Raman optical activity (ROA) spectroscopy is a promising analytical method for studying the structure and conformation of polypeptides and proteins in solution. However, the structural information obtained from such vibrational spectra is only indirect and theoretical studies are often necessary to identify how the structure determines the observed spectra. One particular target is the identification and discrimination of different helical secondary structure elements. Herein, a theoretical investigation of the ROA spectra of a series of 3(10)-helical polypeptides is presented. In particular, the effect of chain length, C(α)-substitution pattern, the introduction of larger aliphatic side chains, and the variation of their conformation on the ROA spectra is studied. To extract general principles from these calculations, the positions, intensities, and shapes of the ROA bands are analyzed in terms of localized modes, which makes it possible to identify possible ROA signatures of 3(10) -helical structures, but also provides fundamental insight into the generation of ROA signals in complex polypeptides. Finally, the calculated spectra can be compared to the previously reported ROA spectrum of a specifically designed 3(10) -helical heptapeptide. This allows most of the features in the experimental spectrum to be assigned.

Synthesis and Reactivity Comparisons of 1‐Methyl‐3‐Substituted Cyclopropene Mini‐tags for Tetrazine Bioorthogonal Reactions

“…Such localized modes can be obtained by performing a unitary transformation of the normal modes51 and have previously been established as a tool for analyzing (harmonic) vibrational spectra of large molecules 15. 16, 52–54 A detailed description for the methodology for localizing vibrational normal modes was presented previously,51 and we will, therefore, only provide a brief overview.…”

Inspecting chiral molecules by Raman optical activity spectroscopy

“…69 Indeed, ROA was proposed as suitable for an analysis of 3 10 -helical peptides. 70 For the valinomycine peptide, where the CCT transfer technique was used, populations of conformations "invisible" by NMR could be estimated. 4j Remarkably, fully ab initio simulation of the b-domain of rat metallothionein protein provided ROA intensities well comparable with the experiment.…”

Optically Active Vibrational Spectroscopy of α‐Aminoisobutyric Acid Foldamers in Organic Solvents and Phospholipid Bilayers

“…Crucially, both VCD and ROA should provide information about the absolute helical sense, which is especially important for foldamers and peptaibols with large proportions of achiral Aib but very few chiral residues. VCD studies have been performed on right‐handed 3 10 ‐helical peptides (negatively signed bands at ≈1680 and 1520 cm −1 and positive at ≈1660 cm −1 ), but only one instance of ROA analysis of a 3 10 ‐helical peptide has been reported: studies in water on a polar heptapeptide with a propensity to adopt a right‐handed screw sense suggested a potential marker band for 3 10 ‐helix secondary structure at 1668 cm −1 (with positive sign), which was corroborated by theoretical modelling …”

“…[30,31] Crucially,b oth VCD and ROA should provide information aboutt he absolute helical sense, which is especially important for foldamers and peptaibols with large proportions of achiral Aib but very few chiral residues.V CD studies have been performed on right-handed 3 10 -helicalp eptides (negatively signed bands at % 1680 and 1520 cm À1 and positive at % 1660cm À1 ), [31] buto nly one instance of ROA analysis of a3 10 -helicalp eptideh as been reported:s tudies in water on ap olar heptapeptide with ap ropensity to adopt ar ight-handeds crew sense suggested ap otential marker band for 3 10 -helix secondary structure at 1668 cm À1 (with positive sign), [32] which was corroborated by theoretical modelling. [33] To explore how this proposed 3 10 -helix marker band could be exploited for the conformational analysis of Aib foldamers in different apolare nvironments (the reported ROA marker band was determined in water), we have performed Raman, ROA, IR and VCD spectroscopic studies on as eries of homologous achiral foldamers and chiral derivatives (Figure 1a,b). These studies aimed to show how optically active vibrational spectroscopies can determine both the relative proportion and chiral sense of 3 10 -helical structure in Aib foldamers, both in organic solvents and bilayer membranes.…”