Date of Award

5-2019

Document Type

Thesis open access

Department

Chemistry

First Advisor

Adam R. Urbach

Second Advisor

Laura Hunsicker-Wang

Abstract

Sequence-selective recognition is an important goal for synthetic receptors binding to proteins with a high affinity. This thesis describes the molecular recognition of methionine-terminated peptides by the synthetic receptor, cucurbit[8]uril (Q8) with submicromolar affinity in aqueous solution. Previous studies have demonstrated Q8 binding to N-terminal aromatic residues. In 2015 we discovered that Q8 can bind to certain dipeptide sequences with both side chains binding simultaneously with the cavity of Q8. The additional binding interface of the two residues suggested the possibility of targeting entirely nonaromatic peptides. To test this hypothesis, a peptide library was designed by qualitatively screening for Q8 binding though a fluorescent indicator displacement assay. The results revealed several leads from the Met-terminated series, suggesting strong binding which was characterized using isothermal titration calorimetry, 1H NMR spectroscopy, and mass spectrometry. This discovery of Q8 binding to Met-terminated peptides, which contained non-aromatic sequences, incited a detailed investigation of 25 peptides to characterize the structural determinants of binding. Further work in inhibiting a non-selective protease using Q8 to bind these dipeptide sequences is ongoing.

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