A Computational Protocol for Vibrational Circular Dichroism Spectra of Cyclic Oligopeptides

Abstract

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 ( 32073075 Phys. Chem. Chem. Phys. 2020 22 7169 7192 and 30943025 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.

Can the absolute configuration of cyclic peptides be determined with vibrational circular dichroism?

“…38 For more details on the computational protocol, we refer to our previous work. 18 Replication data for this work including geometries and Boltzmann averages are available at DataverseNO. 31…”

“…In order to investigate to what extent the AC of cyclic peptides can be determined with VCD, we use our previously published computational protocol 18 to compute VCD spectra for all stereoisomers of a given cyclic peptide and compare them to an experimental VCD spectrum of a stereoisomer with known AC.…”

“…15 This was facilitated by the fairly rigid structure of these molecules. The situation becomes more complex and challenging for conformationally flexible systems such as cyclic peptides, 18 where VCD alone may not be successful in an unambiguous AC determination. For cyclic peptides, an additional complication may arise from the fact that the dominating VCD bands of these molecules are amide modes in which the chiral centers are not significantly involved, the bands instead reflect the secondary structure of the peptides.…”

“…A computational protocol to simulate the spectra typically consists of a conformational search and quantum-chemical calculations of the VCD spectra. 8,18 Since the spectra are measured in solution, the solvent environment is often included in calculations through the use of a continuum model. 21,22 The conformational search is a key step in the computational protocol for flexible molecules, since different conformers with the same AC may provide VCD intensities with different signs in the same frequency range.…”

“…When relevant conformers are missing, this can easily lead to an erroneous assignment of the AC. In a previous work, 18 we established a reliable computational protocol for the calculation of conformationally flexible molecules with known AC, using several cyclic peptides as test systems. This computational protocol was based on a meta-dynamics conformational search as implemented in CREST, [23][24][25] combined with energies, geometries and VCD spectra obtained using DFT.…”