Well-Tempered Metadynamics Simulations Predict the Structural and Dynamic Properties of a Chiral 24-Atom Macrocycle in Solution

Abstract

Inspired 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 1 H NMR. Simulations suggest that the macrocycle exists as a rapidly interconverting pair of enantiomeric, folded structures. Experimentally, 1 H 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.

Computational and Experimental Evidence for Templated Macrocyclization: The Role of a Hydrogen Bond Network in the Quantitative Dimerization of 24-Atom Macrocycles

“…This situation could not be dismissed readily as the result of constraints imposed by cyclization. Computational models using well-tempered metadynamics suggested that these macrocycles can adopt multiple conformations [ 26 ]. The physical manipulation of Corey–Pauling–Koltun models corroborated these conclusions.…”

A Model for the Rapid Assessment of Solution Structures for 24-Atom Macrocycles: The Impact of β-Branched Amino Acids on Conformation

“…In addition, variable-temperature NMR experiments reveal markedly different behavior among this series of macrocycles. We have reported that G-G moves between two folded, enantiomeric states 48 by way of an extended structure. 49 Importantly, these two states interconvert the axial and equatorial positions of α-H, B and C protons much like the ring-flip in cyclohexane.…”

Controlling Swing Rates in Macrocyclic Molecular Mortise Hinges

“… [37–40] The synthesis and characterization of 1 has been described [38] . The preparation of 2 follows the same route [38] …”

“…[37][38][39][40] The synthesis and characterization of 1 has been described. [38] The preparation of 2 follows the same route. [38] Briefly, the monomers are obtained in two steps starting with the one-pot, sequential substitution of trichlorotriazine to yield the carboxylic acid intermediate.…”

“…[38] The preparation of 2 follows the same route. [38] Briefly, the monomers are obtained in two steps starting with the one-pot, sequential substitution of trichlorotriazine to yield the carboxylic acid intermediate. Substitution commences with additions of BOC-hydrazine, followed by the amino acid of interest and a third auxiliary amine.…”