Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 133, Issue 6, Pages 1987-2001Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ja1100867
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Funding
- Royal Society
- EPSRC
- BBSRC [BB/E004350/1] Funding Source: UKRI
- EPSRC [EP/G026688/1, EP/I500200/1, EP/E000614/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/C510824/1, BB/E004350/1, EGA17763] Funding Source: researchfish
- Engineering and Physical Sciences Research Council [EP/E000614/1, EP/D023335/1, GR/T26542/01, EP/G026688/1, EP/I500200/1, EP/D023343/1] Funding Source: researchfish
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Cyclodextrins (CDs) have been widely used in host-guest molecular recognition because of their chiral and hydrophobic cavities. For example, beta-cyclodextrin (beta CD) lodged as a molecular adaptor in protein pores such as a-hemolysin (alpha HL) is used for stochastic sensing. Here, we have tuned the cavity and overall size of beta CD by replacing a single oxygen atom in its ring skeleton by a disulfide unit in two different configurations to both expand our ability to detect analytes and understand the interactions of beta CD with protein pores. The three-dimensional structures of the two stereoisomeric CDs have been determined by the combined application of NMR spectroscopy and molecular simulation and show distorted conformations as compared to natural beta CD. The interactions of these synthetic beta CD analogues with mutant alpha HL protein pores and guest molecules were studied by single-channel electrical recording. The dissociation rate constants for both disulfide CDs from the mutant pores show similar to 1000-fold increase as compared to those of unaltered beta CD, but are similar to 10-fold lower than the dissociation rate constants for beta CD from wild-type alpha HL. Both of the skeleton-modified CDs show altered selectivity toward guest molecules. Our approach expands the breadth in sensitivity and diversity of sensing with protein pores and suggests structural parameters useful for CD design, particularly in the creation of asymmetric cavities.
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