Illuminating the dark conformational space of macrocycles using dominant rotors
| Autor: | Diego B. Diaz, Timothy J. McTiernan, Andrei K. Yudin, Anastasia F. Bogdanchikova, Gabriel dos Passos Gomes, Yury Lebedev, Solomon D. Appavoo |
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| Rok vydání: | 2021 |
| Předmět: |
Macrocyclic Compounds
Magnetic Resonance Spectroscopy Protein Conformation 010405 organic chemistry Chemistry General Chemical Engineering Bioactive molecules General Chemistry Nuclear magnetic resonance spectroscopy Crystallography X-Ray 010402 general chemistry Space (mathematics) Peptides Cyclic 01 natural sciences 0104 chemical sciences Rotational energy Turn (biochemistry) Chemical physics Thermodynamics Molecule Density functional theory Amino Acid Sequence Amino acid residue Density Functional Theory |
| Zdroj: | Nature Chemistry. 13:218-225 |
| ISSN: | 1755-4349 1755-4330 |
| DOI: | 10.1038/s41557-020-00620-y |
| Popis: | 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. Constrained molecules typically adopt one major conformation and this limitation prevents the study of other energetically less-favourable conformations. Nevertheless, these alternate structures might prove to be useful and it has now been shown that a dominant rotor method can alter the energetic landscape of peptides to create two-well systems with distinct conformational behaviour. |
| Databáze: | OpenAIRE |
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