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dc.creatorCapelli R.
dc.creatorMenke A.J.
dc.creatorPan H.
dc.creatorJanesko B.G.
dc.creatorSimanek E.E.
dc.creatorPavan G.M.
dc.description.abstractInspired by therapeutic potential, the molecular engineering of macrocycles is garnering increased interest. Exercising control with design, however, is challenging due to the dynamic behavior that these molecules must demonstrate in order to be bioactive. Herein, the value of metadynamics simulations is demonstrated: the free-energy surfaces calculated reveal folded and flattened accessible conformations of a 24-atom macrocycle separated by barriers of ?6 kT under experimentally relevant conditions. Simulations reveal that the dominant conformer is folded?an observation consistent with a solid-state structure determined by X-ray crystallography and a network of rOes established by 1H NMR. Simulations suggest that the macrocycle exists as a rapidly interconverting pair of enantiomeric, folded structures. Experimentally, 1H NMR shows a single species at room temperature. However, at lower temperature, the interconversion rate between these enantiomers becomes markedly slower, resulting in the decoalescence of enantiotopic methylene protons into diastereotopic, distinguishable resonances due to the persistence of conformational chirality. The emergence of conformational chirality provides critical experimental support for the simulations, revealing the dynamic nature of the scaffold?a trait deemed critical for oral bioactivity. © 2022 American Chemical Society. All rights reserved.
dc.sourceACS Omega
dc.subjectChemical structureen_US
dc.subjectMolecular structureen_US
dc.titleWell-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution
dc.rights.holder2022 The Authors
dc.rights.licenseCC BY 4.0
local.collegeCollege of Science and Engineering
local.departmentChemistry and Biochemistry
local.personsMenke (CHEM), Janesko (CHEM), Simanek (CHEM)

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