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Interpreting vibrational circular dichroism spectra: the Cai•factor for absolute configuration with confidence.

ABSTRACT: Vibrational circular dichroism (VCD) spectroscopy can generate the data required for the assignment of absolute configuration, but the spectra are hard to interpret. We have recorded VCD data for thirty pairs of small organic compounds and we use this database to validate a method for the automated analysis of VCD spectra and the assignment of absolute configuration: the Cai•factor (Configuration: absolute information). The analysis of the data demonstrates that the procedure is a reliable and time-efficient method for determination of absolute configuration, which gives both the assignment and a measure of confidence in the outcome, even when the spectra are imperfect. The majority of molecules tested have a high confidence score and all of these have the correct assignment.

SUBMITTER: Lam J

PROVIDER: S-EPMC10031863 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Interpreting vibrational circular dichroism spectra: the Cai•factor for absolute configuration with confidence.

Lam Jonathan J Lewis Richard J RJ Goodman Jonathan M JM

Journal of cheminformatics 20230321 1

Vibrational circular dichroism (VCD) spectroscopy can generate the data required for the assignment of absolute configuration, but the spectra are hard to interpret. We have recorded VCD data for thirty pairs of small organic compounds and we use this database to validate a method for the automated analysis of VCD spectra and the assignment of absolute configuration: the Cai•factor (Configuration: absolute information). The analysis of the data demonstrates that the procedure is a reliable and t ...[more]

PMID: 36945031

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Project description:Cyclic peptides are a promising class of compounds for next-generation antibiotics as they may provide new ways of limiting antibiotic resistance development. Although their cyclic structure will introduce some rigidity, their conformational space is large and they usually have multiple chiral centers that give rise to a wide range of possible stereoisomers. Chiroptical spectroscopies such as vibrational circular dichroism (VCD) are used to assign stereochemistry and discriminate enantiomers of chiral molecules, often in combination with electronic structure methods. The reliable determination of the absolute configuration of cyclic peptides will require robust computational methods than can identify all significant conformers and their relative population and reliably assign their stereochemistry from their chiroptical spectra by comparison with ab initio calculated spectra. We here present a computational protocol for the accurate calculation of the VCD spectra of a series of flexible cyclic oligopeptides. The protocol builds on the Conformer-Rotamer Ensemble Sampling Tool (CREST) developed by Grimme and co-workers ( Phys. Chem. Chem. Phys. 2020, 22, 7169-7192 and J. Chem. Theory. Comput. 2019, 15, 2847-2862) in combination with postoptimizations using B3LYP and moderately sized basis sets. Our recommended computational protocol for the computation of VCD spectra of cyclic oligopeptides consists of three steps: (1) conformational sampling with CREST and tight-binding density functional theory (xTB); (2) energy ranking based on single-point energy calculations as well as geometry optimization and VCD calculations of conformers that are within 2.5 kcal/mol of the most stable conformer using B3LYP/6-31+G*/CPCM; and (3) VCD spectra generation based on Boltzmann weighting with Gibbs free energies. Our protocol provides a feasible basis for generating VCD spectra also for larger cyclic peptides of biological/pharmaceutical interest and can thus be used to investigate promising compounds for next-generation antibiotics.

Dataset Information

Interpreting vibrational circular dichroism spectra: the Cai•factor for absolute configuration with confidence.

Publications

Interpreting vibrational circular dichroism spectra: the Cai•factor for absolute configuration with confidence.

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