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Illuminating the dark conformational space of macrocycles using dominant rotors

Abstract

Three-dimensional conformation is the primary determinant of molecular properties. The thermal energy available at room temperature typically equilibrates the accessible conformational states. Here, we introduce a method for isolating unique and previously understudied conformations of macrocycles. The observation of unusual conformations of 16- to 22-membered rings has been made possible by controlling their interconversion using dominant rotors, which represent tunable atropisomeric constituents with relatively high rotational barriers. Density functional theory and in situ NMR measurements suggest that dominant rotor candidates for the amino-acid-based structures considered here should possess a rotational energy barrier of at least 25 kcal mol−1. Notable differences in the geometries of the macrocycle conformations were identified by NMR spectroscopy and X-ray crystallography. There is evidence that amino acid residues can be forced into rare turn motifs not observed in the corresponding linear counterparts and homodetic rings. These findings should unlock new avenues for studying the conformation–activity relationships of bioactive molecules.

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Fig. 1: Landscape remodelling can stabilize conformations in the dark space.
Fig. 2: Dominant rotors as a means to explore complex energy landscapes of constrained chains of rotors.
Fig. 3: Structural properties of the dominant rotor-containing macrocycles.
Fig. 4: Illuminating unusual conformations and properties using dominant rotors.
Fig. 5: Observation of unusual conformations in 22-membered rings enabled by a trimethylated dominant rotor.

Data availability

Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 1956029 (11b), 1956026 (11c), 1956027 (Sa-11e), 1956031 (Ra-11e), 1956032 (Ra-12c), 1956038 (Sa-12c), 1956030 (Sa-13b) and 1956028 (Sa-13c). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/. The .xyz files with outputs of all DFT and xtb calculations performed in this study are contained in the .zip file named SI_data.zip, and are also hosted on the following GitHub page: https://github.com/gabegomes/Illuminating-the-dark-conformational-space-using-dominantrotors. The dihedral angle data used to construct the Ramachandran plots of the compounds in this article are reported in Section 1.1.12 of the Supplementary Information. Correspondence and requests for materials should be addressed to A.K.Y.

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Acknowledgements

We thank the Natural Sciences and Engineering Research Council (NSERC) for financial support. D.B.D. and S.D.A. thank the NSERC for PGS-D funding. G.P.G. thanks the NSERC for a Banting Postdoctoral Fellowship. We thank A. J. Lough for X-ray structure determination and D. C. Burns of the CSICOMP NMR facility for assistance with spectroscopic experiments. We thank Compute Canada for computational resources. DFT and NBO computations were performed on the Niagara supercomputer at the SciNet HPC Consortium. SciNet is funded by the Canada Foundation for Innovation, the Government of Ontario, Ontario Research Fund - Research Excellence and the University of Toronto. Helpful discussions with R. Mendoza-Sanchez, C. C. G. Scully, A. Holownia, S. K. Liew, H. S. Soor, C. N. Apte and A. L. Roughton are greatly appreciated. We also thank A. Aspuru-Guzik, K. Z. Demmans, S. C. Khojasteh, L. A. Dutra, F. Sprang and B. Hamzaev for their help on ongoing projects related to the use of the dominant rotors described here.

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Contributions

A.K.Y. and D.B.D. conceived the study and designed the experiments; D.B.D., A.F.B., Y.L. and T.J.M. carried out macrocycle synthesis, purification and characterization; D.B.D. obtained and analysed the kinetic and thermodynamic data; S.D.A. and D.B.D. computed the NMR-based structures and performed unrestrained MD simulations; Y.L. and D.B.D. obtained X-ray quality crystals of the macrocycles; G.P.G. performed DFT and NBO calculations; D.B.D. and A.K.Y. wrote the paper with help from all the authors.

Corresponding author

Correspondence to Andrei K. Yudin.

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Extended data

Extended Data Fig. 1 Characterization of dominant rotor-containing macrocyclic peptides.

a, 2D Exchange spectroscopy of 11b (top) and 11c (bottom) in DMSO-d6 at 25 °C. The negative cross-peak in the spectrum of 11b suggests an exchange between two conformers on the NMR time scale due to atropisomerism at the biaryl rotor71,72. b, LC-MS chromatograms of linear starting material Fmoc-Trz-AGF (top), Ra-12c (middle) and Sa-12c (bottom) atropdiastereomeric macrocycles.

Extended Data Fig. 2 Hydrogen-deuterium exchange of the backbone amide groups of Sa- and Ra-11e.

Differences in amide NH hydrogen-deuterium exchange rates and chemical shift/temperature coefficients show that dominant rotors can stabilize distinct solution conformations.

Extended Data Fig. 3 Contrasting the structural features of dominant rotor peptides and homodetic counterparts.

a, Hydrogen-bonding profile and temperature-chemical shift coefficients (Tcoeff) of homodetic peptide 15 and dominant rotor 12c macrocycles, based on the AGF sequence, as measured by VT 1H NMR spectroscopy. Hydrogen atoms engaged in intramolecular hydrogen bonding and their corresponding NMR signals are highlighted here by grey rectangles. b, Frequency histograms of the AGF conformation over the unrestrained MD trajectory revealed a large population shift in 15 relative to 12c. The macrocycle flexibility in the dominant rotor peptides was assessed computationally and deduced to be minimal, with average backbone atom deviations below 0.2 Å. Both Ra- and Sa-12c structures were stabilized by 13-membered hydrogen bonds with lengths (Å) of 2.3 ± 0.7 and 2.4 ± 1.0, respectively, over the course of the 100ns MD trajectories. An overlay of the backbone atoms for the 10 lowest energy clusters in each peptide shows that dominant rotor peptide conformations are closely matched and are well-behaved in solution. Side chains are omitted for clarity. c, An overlay of the X-ray crystal structure (grey) and NMR solution structure (blue) of compound Ra-12c show a close overlap between the solid- and solution-phase structures. d, Energetic contribution of hydrogen bonds to conformational stabilization in Ra-12c. Hydrogen bond distances (Å): α, 1.85; β, 2.71. Second-order stabilization energies (in kcal mol−1): α, 9.1; β, < 0.5. NBO analysis of nOσ*NH interactions between the dominant rotor carbonyl and transannular amides. e, The NBO interaction of the nOπ*CO between the dominant rotor and Ala1 was calculated to be 2.8 kcal mol−1 with an O•••C distance of 2.65 Å and OCO angle of 103.4º.

Extended Data Fig. 4 Generality of hydrogen-bonding patterns across dominant rotor-containing macrocycles.

a, Structural scope of dominant rotor peptides with Ra-(red) and Sa-(grey) average backbone solution structures superimposed on the three consecutive natural amino acid residues. Root mean-squared deviation (RMSD) shown for macrocycle backbone atoms. The type II αRU-turn was detected in every Ra-well except for 12h, which exhibited a left-handed helical turn. Apart from 12g, the Sa-wells are variable and access a variety of different turn types and conformations containing non-hydrogen bonded amides. Dominant rotor omitted for clarity. Gibbs free energy differences in kcal mol−1 are shown in brackets.

Extended Data Fig. 5 Choosing bis-methylated dominant rotors can result in additional differentiation of the observed conformational states.

Replacement of the mono-methyl dominant rotor in 12c with a bis-methylated rotor disrupts α-turn formation and stabilizes a non-classical β-turn type in Ra-12d (grey). This conformational change in the Ra-well is supported by a decrease in the coupling constant (3JHNCH) of the alanine NH residue from 5.3 to 2.3 Hz. The increase from 4.7 to 7.7 Hz in the Sa-well also indicates a change in the alanine ϕ dihedral angle of Sa-12d (green). Ramachandran plots of the three α-carbon atoms in the AGF sequence of the 10 lowest energy clusters for each dominant rotor peptide show that the Ra-12d conformer is less scattered than Sa-12d, and therefore more rigid.

Extended Data Fig. 6 Observation of unusual conformations in 22-membered rings.

Arrow diagram of the PGLGF (proline-glycine-leucine-glycine-phenylalanine) sequence shows that Gly2 and Phe5 adopt vastly different backbone conformations in two-well system 14c. The NMR-solution structure of Ra-14c (cyan) shows that the dominant rotor carbonyl engages the Gly2 amide NH in an inverse γ-turn, which enforces a type I-αLS turn for the LGF segment. Sa-14c (green) adopts a novel π-turn with an internal β-turn that is stabilized by a hydrogen bond between the carbonyl oxygen and amide NH of the dominant rotor. VT NMR studies are in agreement with these unique hydrogen-bond patterns.

Supplementary information

Supplementary Information

Supplementary Methods, Discussion, Figs. 1–13, Tables 1 and 2, Appendix 1: NMR spectra, Appendix 2: X-ray coordinate data, Appendix 3: torsion scan coordinate data, Appendix 4: NBO coordinate data.

Supplementary Data 1

.xyz files of the geometries obtained from DFT calculations.

Supplementary Data 2

Crystallographic data for compound 11c. CCDC reference 1956026.

Supplementary Data 3

Crystallographic data for compound Sa-11e. CCDC reference 1956027.

Supplementary Data 4

Crystallographic data for compound Sa-13c. CCDC reference 1956028.

Supplementary Data 5

Crystallographic data for compound 11b. CCDC reference 1956029.

Supplementary Data 6

Crystallographic data for compound Sa-13b. CCDC reference 1956030.

Supplementary Data 7

Crystallographic data for compound Ra-11e. CCDC reference 1956031.

Supplementary Data 8

Crystallographic data for compound Ra-12c. CCDC reference 1956032.

Supplementary Data 9

Crystallographic data for compound Sa-12c. CCDC reference 1956038.

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Diaz, D.B., Appavoo, S.D., Bogdanchikova, A.F. et al. Illuminating the dark conformational space of macrocycles using dominant rotors. Nat. Chem. 13, 218–225 (2021). https://doi.org/10.1038/s41557-020-00620-y

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