Solid‐State Conformational Flexibility at Work: Zipping and Unzipping within a Cyclic Peptoid Single Crystal

Meli, Alessandra; Macedi, Eleonora; Riccardis, Francesco De; Smith, Vincent J.; Barbour, Leonard J.; Izzo, Irene; Tedesco, Consiglia

doi:10.1002/ange.201511053

Cited by 10 publications

(8 citation statements)

References 44 publications

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“…Upon reinjection, the samples equilibrated to provide a mixture of peaks, consistent with multiple slowly-interconverting conformations at room temperature. Several research groups have shown that 6-residue (18-member) macrocycles containing proline exhibit multiple slowly-interconverting conformations at room temperature; [21][22][23] however, these conformations can be biased by internal steric interactions such as a well-placed methyl group 24 or via external sources such as cation-carbonyl interactions. Q-Pro containing macrocycles contain more functional groups than these previously described macrocycles.…”

Section: Resultsmentioning

confidence: 99%

“…Several research groups have shown that 6-residue (18-member) macrocycles containing proline exhibit multiple slowly interconverting conformations at room temperature; − however, these conformations can be biased by internal steric interactions such as a well-placed methyl group or via external sources such as cation-carbonyl interactions. To test whether QPM could adopt well-defined structures in a solution, we screened multiple metal triflates against QPM- 3 (Figure B).…”

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confidence: 99%

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Metal-Binding Q-Proline Macrocycles

et al. 2021

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Herein, we introduce the efficient synthesis of Q-proline (Q-Pro) based, metal-binding macrocycles (QPM), which can display up to nine functional groups. Synthesis of eight QPM was achieved through standard Fmoc-SPPS and peptoid chemistry. QPM are disordered in the absence of a metal cation, as evidenced by NMR and a crystal structure of QPM-3 obtained through racemic crystallization. Addition of metal cations cause these macrocycles to adopt ordered, uniform core structures regardless of the functional groups. Alkylation of QPM allows for addition of reactive functional groups as the final step in a synthesis. Interestingly, the addition of secondary functional groups to the hydantoin amide position (R2) converts the proline ring from C-endo to C-exo, due to steric interactions. 27 Pro 3-2 60 No >98 28 3-4 60 Yes 50 29 3-4 60* Yes >98 QP9 QP9 30 3-4 60* Yes >98 QP15

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Section: Resultsmentioning

confidence: 99%

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confidence: 99%

Metal-Binding Q-Proline Macrocycles

et al. 2021

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“…Just as cyclization is known to stabilize folded peptide conformations, [20][21][22][23][24] so have similar strategies been successful at achieving pre-organized spiroligomer 25 and peptoid macrocycles. [26][27][28][29][30][31][32][33][34] Indeed, preorganization due to cyclization helps explain the prevalence of cyclic designs in the modest corpus of peptoid crystal structures that have been solved to date. 1 Interestingly, it has been found that cyclic peptoids can host metal cation adducts through the coordination of backbone carbonyl groups, 31,35 reminiscent of natural products such as mycotoxins.…”

Section: Introductionmentioning

confidence: 99%

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Hurley¹,

Northrup²,

Ge³

et al. 2021

Preprint

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<div>The rational design of foldable and functionalizable peptidomimetic scaffolds requires the concerted application of both computational and experimental methods. Recently, a new class of designed peptoid macrocycle incorporating spiroligomer proline mimics (Q-prolines) has been found to pre-organize when bound by monovalent metal cations. To determine the solution-state structure of these cation-bound macrocycles, we employ a Bayesian inference method (BICePs) to reconcile enhanced-sampling molecular simulations with sparse ROESY correlations from experimental NMR studies. The BICePs approach circumvents the need for bespoke force field parameterization, instead relying on experimental restraints to help narrow the possible set of cis/trans amide isomers in solution. Conformations predicted to be most populated in solution were then simulated in the presence of explicit cations to yield trajectories with observed binding events, revealing a highly-preorganized all-trans amide conformation, whose formation is likely limited by the slow rate of cis/trans isomerization. Interestingly, this conformation differs from a racemic crystal structure solved in the absence of cation. Free energies of cation binding computed from distance-dependent potentials of mean force suggest Na+ has higher affinity to the macrocycle than K+, with both cations binding much more strongly in acetonitrile than water. The simulated affinities are able to correctly rank the extent to which different macrocycle sequences exhibit preorganization in the presence of different metal cations and solvents, suggesting our approach is suitable for solution-state computational design.</div>

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“…The presence of solvent molecules is known to be crucial in determining the resulting crystal form. The employment of different crystallization solvents can produce indeed different crystal forms, where the solvent molecules could affect the solid state assembly [4,5]. The effect of the solvent can indeed influence the growth, the morphology and the packing of crystal structures [6][7][8][9][10][11][12][13][14], so that the same ligand can crystallize in different forms [4].…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure, Hirshfeld Surface Analysis and Energy Framework Calculations of Different Metal Complexes of a Biphenol-based Ligand: Role of Solvent and Transition Metal Ion

Macedi¹,

Rossi²,

Formica³

et al. 2023

Preprint

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A new Pd(II) complex of the previously reported ligand N,N′-bis[(2,2′-dihydroxybiphen-3-yl)methyl]-N,N′-dimethylethylenediamine (L) was obtained from a DMF/H2O mixture. It differs from a Pd(II) complex of L previously obtained by sole DMF. The roles in the solid state assembly of solvent molecules and molecular conformation (driven by specific transition metal ions) were studied by comparing six complexes of L containing different metal centers (Ni(II), Cd(II), Cu(II), Pd(II)). Hirshfeld surface analysis, 2D fingerprint plots and energy frameworks calculations were used to investigate the intermolecular interactions within the crystal packing of the six complexes. As suggested by interaction energies, Pd(II) and Ni(II) complexes arrange to form ribbons, while Cd(II) and Cu(II) complexes form 3D networks. Interactions between complexes and solvent molecules in the previous Pd(II) complex are replaced by complex-complex interactions in the new Pd(II) complex, while BuOH and MeOH are interchangeable in the interactions within the crystal packing of the two Ni(II) complexes. Finally, solvent molecules are not involved in the crystal packing of the Cu(II) complex. The present study suggested that the solid state assembly of these systems is mainly driven by the molecular conformation, that depends in turn by the metal ion involved, while the solvent only plays a minor role.

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Solid‐State Conformational Flexibility at Work: Zipping and Unzipping within a Cyclic Peptoid Single Crystal

Cited by 10 publications

References 44 publications

Metal-Binding Q-Proline Macrocycles

Metal-Binding Q-Proline Macrocycles

Metal Cation-Binding Mechanisms of Q-Proline Peptoid Macrocycles in Solution

Crystal Structure, Hirshfeld Surface Analysis and Energy Framework Calculations of Different Metal Complexes of a Biphenol-based Ligand: Role of Solvent and Transition Metal Ion

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