Emergence of low-symmetry foldamers from single monomers

Pappas, Charalampos G.; Mandal, Pradeep K.; Liu, Bin; Kauffmann, Brice; Miao, Xiaoming; Komáromy, Dávid; Hoffmann, Waldemar; Manz, Christian; Chang, Rayoon; Li, Kai; Pagel, Kevin; Huc, Ivan; Otto, Sijbren

doi:10.1038/s41557-020-00565-2

Cited by 56 publications

(62 citation statements)

References 43 publications

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“…The dipeptide is composed of a modified phenylalanine (p-NH 2 substituted) and a lysine amino-acid residue and is zwitterionic at neutral pH. 20 We have since discovered that relatively small changes in environmental conditions can affect the formation of the folded structure. Libraries made from 2.0 mM building block 1 in the presence of 1.0 M sodium bromide led to the emergence of the hexamer macrocycle ( Figure 1 a), as evident from ultraperformance liquid chromatography/mass spectrometry (UPLC/MS) analysis.…”

Section: Resultsmentioning

confidence: 99%

“…The fact that very specific ring sizes form is in line with previous observations for self-replicating systems (which tend to form the ring size for which multivalency is just sufficient to allow self-assembly) 22 and foldamers (for which different folds often have substantially different energies, so a particular fold and accompanying ring size tend to form with high selectivity). 20 …”

Section: Resultsmentioning

confidence: 99%

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Two Sides of the Same Coin: Emergence of Foldamers and Self-Replicators from Dynamic Combinatorial Libraries

et al. 2021

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The ability of molecules and systems to make copies of themselves and the ability of molecules to fold into stable, well-defined three-dimensional conformations are of considerable importance in the formation and persistence of life. The question of how, during the emergence of life, oligomerization reactions become selective and channel these reactions toward a small number of specific products remains largely unanswered. Herein, we demonstrate a fully synthetic chemical system where structurally complex foldamers and self-replicating assemblies emerge spontaneously and with high selectivity from pools of oligomers as a result of forming noncovalent interactions. Whether foldamers or replicators form depends on remarkably small differences in building block structures and composition and experimental conditions. We also observed the dynamic transformation of a foldamer into a replicator. These results show that the structural requirements/design criteria for building blocks that lead to foldamers are similar to those that lead to replicators. What determines whether folding or replication takes place is not necessarily the type of noncovalent interaction, but only whether they occur intra- or intermolecularly. This work brings together, for the first time, the fields of replicator and foldamer chemistry.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Two Sides of the Same Coin: Emergence of Foldamers and Self-Replicators from Dynamic Combinatorial Libraries

et al. 2021

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“…For example, α/β-peptides which are faithful α-helix mimics have been developed as inhibitors of protein-protein interactions or as receptor ligands with improved pharmacological properties, increased resistance to proteolytic degradation and in some cases prolonged duration of action in vivo (Boersma et al, 2011;Checco et al, 2015;Cheloha, Maeda, Dean, Gardella, & Gellman, 2014;Horne et al, 2009;Johnson et al, 2014;Johnson & Gellman, 2013;Kritzer, Hodsdon, & Schepartz, 2005;Kritzer, Stephens, Guarracino, Reznik, & Schepartz, 2005;Lee et al, 2009;Liu, Cheloha, Watanabe, Gardella, & Gellman, 2018;Liu et al, 2019;Michel, Harker, Tirado-Rives, Jorgensen, & Schepartz, 2009). Furthermore, the ability to link sequence and folding within nonbiological synthetic foldamers can be exploited to create architectures reaching the size and complexity of small proteins (tertiary and quaternary structures) (Horne & Grossmann, 2020;Pappas et al, 2020) or molecular strands that display molecular recognition properties and functions beyond those found in nature (Ferrand & Huc, 2018;Gan et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Urea based foldamers

Yoo

Dolain

et al. 2021

Methods in Enzymology

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“…[7][8][9][10] The evolutionary journey of modern enzyme is intricately related to the emergence of metabolic pathways. 10,[13][14][15][16][17] Deep phylogenetic analyses have suggested the presence of highly conserved enzymes for amino acid and lipid metabolism. 10 Minimal metabolic cycles involved with breaking of activated molecules and accessing of self-aggregated complex structures operating away from equilibrium, could in principle have set the stage for selection and adaptation.…”

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confidence: 99%

Emergence of a Promiscuous Peroxidase Under Non-Equilibrium Conditions

Pal¹,

Reja²,

Bal³

et al. 2021

Preprint

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In the far from equilibrium state of living matter, energy is consumed to fuel the metabolic networks of enzymatic reactions. The emergence of protometabolic pathways in primeval earth is intricately related to the evolutionary journey of modern enzymes. Fundamental understanding of such energy driven generation of early catalytic systems would help us recognize the conditions required for the minimal metabolism that predated the chemical emergence of life. Herein, we report substrate driven generation of a non-equilibrium catalytic machinery from a single amino acid functionalized fatty acid in presence of a cofactor hemin. The non-equilibrium assembled state showed acceleration of catalytic potential resulting in degradation of the substrate and subsequently led to disassembly. Controls that promoted equilibration could not access the three-dimensional microphases and showed substantially lower catalytic activity. Significantly, the assembled state showed latent catalytic function by hydrolysing a precursor to yield the same substrate. Consequently, the assembly was benefitted with augmented lifetime of the catalytic state exploiting a promiscuous cascade and thus foreshadowing protometabolism. The results contribute towards our understanding of energy driven generation of primitive catalytic machineries that assisted the minimal metabolism of early life.

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Emergence of low-symmetry foldamers from single monomers

Cited by 56 publications

References 43 publications

Two Sides of the Same Coin: Emergence of Foldamers and Self-Replicators from Dynamic Combinatorial Libraries

Two Sides of the Same Coin: Emergence of Foldamers and Self-Replicators from Dynamic Combinatorial Libraries

Urea based foldamers

Emergence of a Promiscuous Peroxidase Under Non-Equilibrium Conditions

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