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. 2016 Oct 27:7:13214.
doi: 10.1038/ncomms13214.

Molecular basis of cooperativity in pH-triggered supramolecular self-assembly

Yang Li  1 , Tian Zhao  1 , Chensu Wang  1   2 , Zhiqiang Lin  1 , Gang Huang  1 , Baran D Sumer  3 , Jinming Gao  1
Affiliations

Molecular basis of cooperativity in pH-triggered supramolecular self-assembly

Yang Li et al. Nat Commun. .

Erratum in

Abstract

Supramolecular self-assembly offers a powerful strategy to produce high-performance, stimuli-responsive nanomaterials. However, lack of molecular understanding of stimulated responses frequently hampers our ability to rationally design nanomaterials with sharp responses. Here we elucidated the molecular pathway of pH-triggered supramolecular self-assembly of a series of ultra-pH sensitive (UPS) block copolymers. Hydrophobic micellization drove divergent proton distribution in either highly protonated unimer or neutral micelle states along the majority of the titration coordinate unlike conventional small molecular or polymeric bases. This all-or-nothing two-state solution is a hallmark of positive cooperativity. Integrated modelling and experimental validation yielded a Hill coefficient of 51 in pH cooperativity for a representative UPS block copolymer, by far the largest reported in the literature. These data suggest hydrophobic micellization and resulting positive cooperativity offer a versatile strategy to convert responsive nanomaterials into binary on/off switchable systems for chemical and biological sensing, as demonstrated in an additional anion sensing model.

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Figures

Figure 1
Figure 1. Ultra-pH sensitive (UPS) nanoprobes with unique binary on/off response to pH.
(a) Structure and fluorescence images of a small molecular pH sensor, Lysosensor Green in aqueous solution at different pH. (b) Structure and fluorescence images of a UPS nanoprobe, Rhodamine Green-conjugated PEO-b-PDBA block copolymers in aqueous solution at different pH. (c) Relative fluorescence intensity as a function of pH for Lysosensor Green and PEO-b-PDBA-RhoG nanoprobe. (d) Schematic illustration of pH-triggered binary on/off transition of UPS nanoprobes.
Figure 2
Figure 2. Hydrophobic phase separation drives sharp pH response of UPS copolymers.
(a) Structures of small molecular base dipropylaminoethanol (DPA), polymeric bases of PEI, PEO-b-PDMA and PEO-b-PDPA. (b) pH titration curves of DPA, PEI, PEO-b-PDMA and PEO-b-PDPA. (c) Plot of pH transition sharpness (ΔpH10–90%) as a function of octanol–water partition coefficient (LogP) of small molecular bases (NH4Cl, Chloroquine and DPA) or repeating unit (neutral monomer) of commonly used polybases (poly(ethyleneimine), polylysine, chitosan, polyhistidine) and PEO-b-PR block copolymers. (d) Change of hydrodynamic diameter of UPS nanoprobe PEO-b-PDPA along pH titration coordinate. Significant increase of size indicated the formation of micelles. (e) TEM images of PEO-b-PDPA before (protonation degree at 95%) and after (protonation degree at 85%) critical micelle protonation degree (CMPD=90%). Micelle formation (yellow arrows) was observed when protonation degree was below CMPD. Scale bars, 100 nm.
Figure 3
Figure 3. Divergent proton distribution between unimer and micelle state of PEO-b-PDPA copolymers.
(a) Schematic illustration of dialysis experiments where unimers (22 kD) were separated from micelles (16,000 kD) using a semi-permeable membrane with a molecular weight cutoff of 100 kD. PEO-b-PDMA and PEI were used as negative controls without nanophase separation. Light scattering count rates (b), polymer mass distribution (c) and charges states (d) of different polymers are shown at the protonation degree of 50%. (e) Quantification of unimer and micelle charge states of PEO-b-PDPA at protonation degree of 50%. Protons distributed divergently where unimers were highly charged (∼90%) and micelles were mostly neutral. The experiments were repeated five times, and data are shown in mean±s.d.
Figure 4
Figure 4. Molecular pathway of pH-triggered self-assembly of PEO-b-PDPA copolymers.
(a,b) 1H NMR spectra (in D2O) of methylene protons of PEO-b-PDPA and methyl protons of PEO-b-PDMA adjacent to nitrogen atoms at different protonation degrees, respectively. PEO-b-PDMA was used as negative control without nanophase separation. (c,d) Quantification of chemical shift and peak integration of chosen methyl and methylene protons in PEO-b-PDMA and PEO-b-PDPA, respectively. Integrations were calculated using polyethylene oxide (PEO) segments as internal reference. (e) Schematic illustration of two distinctive deprotonation pathways. Deprotonation of PEO-b-PDMA ammonium groups was gradual along the entire pH titration course. Deprotonation of PEO-b-PDPA ammonium groups displayed a binary copolymer populations consisting of highly charged unimers in solution and neutral copolymers inside micelles.
Figure 5
Figure 5. Model construction to quantify the pH cooperativity.
(a) Micelle-driven deprotonation model with key equations. These equations allow the theoretical-experimental correlation between the microscopic cooperative parameter α and macroscopically measurable pKa. (b,c) Cooperativity analysis based on Hill plot of small molecular base DPA, polymeric bases of PEI, PEO-b-PDMA and PEO-b-PDPA. DPA and PEO-b-PDMA showed non-pH cooperativity. PEI displayed negative pH cooperativity and PEO-b-PDPA showed strong positive cooperativity. (d,e) Cooperativity analysis of PEO-b-PDPA copolymers with different number of repeating units in the hydrophobic segment. Increase of hydrophobic chain length led to stronger positive cooperativity and sharper pH response.
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