The Development of Receptors for Posttranslationally Modified Peptides in Water Public Deposited

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  • March 19, 2019
  • Beaver, Joshua
    • Affiliation: College of Arts and Sciences, Department of Chemistry
  • The work presented in this dissertation highlights recent progress and advances in using dynamic combinatorial chemistry (DCC) for the investigation of molecular recognition in water. In particular, this work emphasizes the selective recognition of posttranslational modifications of histone proteins in the context of peptides through differential non-covalent interactions. DCC was used to identify and synthesize small molecule receptors, in the form of amphiphilic macrocycles with aromatic interiors and anionic exteriors, which bind to modified amino acids with protein-like affinity and selectivity. Advances in supramolecular and materials chemistry continue to expound upon the limits of molecular recognition. The progression of biotechnology in cancer research and the development of green materials, emphasizes the importance of controlling and predicting the non-covalent interactions that drive molecular recognition in water. Understanding posttranslational modifications of histone proteins has been the focus of intense research in recent years, due to their critical involvement in the control of gene transcription. Iterative redesign of a previously identified synthetic receptor that binds to trimethyllysine with affinity and selectivity comparable to the HP1 chromodomain led to the identification of a small molecule receptor with an expanded binding pocket and aromatic surface that recognizes asymmetric dimethylarginine (RaMe2). The size of the binding pocket limited binding to symmetric dimethyl arginine (RsMe2), leading to preferential binding of RaMe2. DCC was also used to conduct a structure function study of previously identified receptors in order to investigate the influences of structure and electrostatic interactions on binding affinity to methylated lysine derivatives. Parallels in relationship to binding pocket depth, were observed between the binding selectivity of native proteins for various methylated lysines and small molecule receptors. The influence of electrostatic interactions on affinity and selectivity revealed that additional carboxylate-ammonium interactions can improve binding affinity, but do not significantly affect selectivity between methylation states of lysine. Non-covalent influences on binding to 3-nitrotyrosine, a product of oxidative stress and important biomarker for disease, were also investigated using DCC. A potential scaffold for selective binding to 3NT over tyrosine was identified and a variety of novel DCC monomers was developed for use in future iterative redesign studies.
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Rights statement
  • In Copyright
  • Johnson, Jeffrey
  • Nicewicz, David
  • Waters, Marcey
  • Brustad, Eric
  • Weeks, Kevin
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
Place of publication
  • Chapel Hill, NC
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