Three Types of Induced Tryptophan Optical Activity Compared in Model Dipeptides: Theory and Experiment

Abstract

The tryptophan (Trp) aromatic residue in chiral matrices often exhibits a large optical activity and thus provides valuable structural information. However, it can also obscure spectral contributions from other peptide parts. To better understand the induced chirality, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and Raman optical activity (ROA) spectra of Trp-containing cyclic dipeptides c-(Trp-X) (where X = Gly, Ala, Trp, Leu, nLeu, and Pro) are analyzed on the basis of experimental spectra and density functional theory (DFT) computations. The results provide valuable insight into the molecular conformational and spectroscopic behavior of Trp. Whereas the ECD is dominated by Trp π-π* transitions, VCD is dominated by the amide modes, well separated from minor Trp contributions. The ROA signal is the most complex. However, an ROA marker band at 1554 cm(-1) indicates the local χ(2) angle value in this residue, in accordance with previous theoretical predictions. The spectra and computations also indicate that the peptide ring is nonplanar, with a shallow potential so that the nonplanarity is primarily induced by the side chains. Dispersion-corrected DFT calculations provide better results than plain DFT, but comparison with experiment suggests that they overestimate the stability of the folded conformers. Molecular dynamics simulations and NMR results also confirm a limited accuracy of the dispersion-DFT model in nonaqueous solvents. Combination of chiral spectroscopies with theoretical analysis thus significantly enhances the information that can be obtained from the induced chirality of the Trp aromatic residue.

Exciton circular dichroism couplet arising from nitrile-derivatized aromatic residues as a structural probe of proteins

“…This is because the far ultraviolet (UV) CD spectrum in the region of 190 – 250 nm [3], arising from the backbone of a polypeptide, depends on the exciton couplings among the individual π-π* and n-π* transitions of its amide units [4]. Similarly, when two amino acids with aromatic sidechains (chromophores) are in close proximity, exciton coupling between their π-π* transition bands ( 1 A 1 - 1 B b transition) could also lead to formation of unique CD signatures in this spectral region [5, 6]. For example, the tryptophan (Trp) residues in the Trpzip β-hairpins give rise to a positive CD band at around 228 nm providing a convenient spectroscopic feature to monitor β-hairpin formation [7–9].…”

First-Principles Predictions of Vibrational Raman Optical Activity of Globular Proteins

“…comes from induced optical activity of the tryptophan residues36,37 and is thus very sensitive to conformational averaging. This and other minor inconsistencies can also be attributed to the anharmonicity and solvent effects that are only partially accounted for by the dielectric CPCM model, and a limited precision of the DFT method causing improper mode ordering.…”

Conformational Effects on the Circular Dichroism of Human Carbonic Anhydrase II: A Multilevel Computational Study

“…The results presented above are in agreement with studies on TEM-1 β-lactamase, which also indicate that structural changes influences both the nature of the mechanisms and the values of the rotational strengths in this enzyme 30,31 . Recently the benefit of implementation of MD together with TDDFT was demonstrated in the case of CD spectra of tryptophan containing cyclic model dipeptides [37].…”

“…[26], [37], [39]) and could contribute for the poor agreement between the calculated and the experimental spectra, more crucially the results might suggest that to calculate the CD properties at reasonable quality it is vitally important to include explicitly the protein environment. In order to test this hypothesis we carried out the matrix method of CD calculations on the tryptophans and tyrosines only (the same system which was used for TDDFT calculations).…”