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. 2017 May 17;139(19):6654-6662.
doi: 10.1021/jacs.7b01357. Epub 2017 May 4.

H-Bond Self-Assembly: Folding versus Duplex Formation

Diego Núñez-Villanueva  1 , Giulia Iadevaia  1 , Alexander E Stross  1 , Michael A Jinks  1 , Jonathan A Swain  1 , Christopher A Hunter  1
Affiliations

H-Bond Self-Assembly: Folding versus Duplex Formation

Diego Núñez-Villanueva et al. J Am Chem Soc. .

Abstract

Linear oligomers equipped with complementary H-bond donor (D) and acceptor (A) sites can interact via intermolecular H-bonds to form duplexes or fold via intramolecular H-bonds. These competing equilibria have been quantified using NMR titration and dilution experiments for seven systems featuring different recognition sites and backbones. For all seven architectures, duplex formation is observed for homo-sequence 2-mers (AA·DD) where there are no competing folding equilibria. The corresponding hetero-sequence AD 2-mers also form duplexes, but the observed self-association constants are strongly affected by folding equilibria in the monomeric states. When the backbone is flexible (five or more rotatable bonds separating the recognition sites), intramolecular H-bonding is favored, and the folded state is highly populated. For these systems, the stability of the AD·AD duplex is 1-2 orders of magnitude lower than that of the corresponding AA·DD duplex. However, for three architectures which have more rigid backbones (fewer than five rotatable bonds), intramolecular interactions are not observed, and folding does not compete with duplex formation. These systems are promising candidates for the development of longer, mixed-sequence synthetic information molecules that show sequence-selective duplex formation.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
H-bonded duplexes formed by oligomers with different recognition units and backbones (R is a solubilizing group). The oligomers are labeled according the type of recognition unit (phosphine oxide = PO, pyridine = N, pyridine N-oxide = NO), the site of attachment of the recognition units (C or N), and the number of atoms separating neighboring recognition units (7, 8, or 9).
Figure 2
Figure 2
Competing equilibria in the formation of a duplex between two complementary oligomers. Intramolecular interactions between recognition sites lead to folding, and intermolecular interactions between multiple oligomers lead to networks of supramolecular aggregates. The effective molarities for folding (EMf) and duplex formation (EMd), the operating concentration (c), and the association constant for formation of a H-bond between two recognition sites (K) determine the distribution of oligomers between the three different assembly channels. The equilibrium constants have additional statistical factors that are not shown.
Figure 3
Figure 3
Chemical structures of the AD 2-mers (R1 = (2-ethylhexyl)oxy; R2 = (2-ethylhexyl)oxy or methoxy; R3 = H or S-β-citronelloxy).
Scheme 1
Scheme 1. Synthesis of Building Blocks 4 and 7
Scheme 2
Scheme 2. Synthesis of C8-NO AD 2-mers
Scheme 3
Scheme 3. Synthesis of C8-PO AD 2-mer (R = (2-Ethylhexyl)oxy)
Scheme 4
Scheme 4. Synthesis of C8-N AD 2-mer (R = (2-Ethylhexyl)oxy)
Scheme 5
Scheme 5. Synthesis of N8-PO AD 2-mer (R = (2-Ethylhexyl)oxy)
Scheme 6
Scheme 6. Synthesis of N7-PO AD 2-mer (R = (2-Ethylhexyl)oxy)
Scheme 7
Scheme 7. Synthesis of C9-PO AD 2-mer
Scheme 8
Scheme 8. Synthesis of Building Blocks 35 and 36
Scheme 9
Scheme 9. Synthesis of C7-PO AA and DD 2-mers (R = S-β-Citronelloxy)
Scheme 10
Scheme 10. Synthesis of C7-PO AD 2-mer for Binding Studies (R = S-β-Citronelloxy)
Scheme 11
Scheme 11. Synthesis of C7-PO AD 2-mer for X-ray Crystallography
Figure 4
Figure 4
Competing equilibria in the assembly of (a) AA·DD and (b) AD·AD duplexes. The equilibrium constants have additional statistical factors that are not shown.
Figure 5
Figure 5
Correlation between χfold estimated using changes in chemical shift (Δδ, eq 11) and association constants (K, eq 8). The line corresponds to y = x.
Figure 6
Figure 6
Lowest energy conformations of AD 2-mers calculated using molecular mechanics conformational searches (MMFFs force-field and CHCl3 solvation implemented in Macromodel).
Figure 7
Figure 7
Single-crystal X-ray structure of 12, which forms a doubly H-bonded duplex in the solid state. Three adjacent unit cells with a total of six molecules of 12 are shown. Hydrogen atoms have been omitted for clarity. The backbones are shown in gray, the H-bond donor recognition units in blue, and the H-bond acceptor units in red.
Figure 8
Figure 8
Single-crystal X-ray structure of 47, which forms a linear H-bonded polymer in the solid state. Three adjacent unit cells with a total of three molecules of 47 are shown. Hydrogen atoms have been omitted for clarity. The backbones are shown in gray, the H-bond donor recognition units in blue, and the H-bond acceptor units in red.
Figure 9
Figure 9
Structures of duplexes formed by AD 2-mers that do not fold (R1 = (2-ethylhexyl)oxy; R2 = S-β-citronelloxy).
See this image and copyright information in PMC

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