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Computational Studies of Noncovalent Interactions in Ligand-Gated Ion Channels – and - Synthesis and Characterization of Red and Near Infrared Cyanine Dyes

Citation

Davis, Matthew Robert (2018) Computational Studies of Noncovalent Interactions in Ligand-Gated Ion Channels – and - Synthesis and Characterization of Red and Near Infrared Cyanine Dyes. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9XK8CQF. http://resolver.caltech.edu/CaltechTHESIS:08182017-161833257

Abstract

This thesis is presented in two parts. The first part, Chapter 2, 3, and 4, offers a series of studies on noncovalent interactions in Ligand Gation Ion Channels (LGICs). The second part describes a series of studies involving the synthesis and characterization of cyanine dyes. The common thread in this work is the use of Density Functional Theory (DFT) to study chemical-scale phenomenon. Chapter 1 offers a brief introduction to DFT and a comparison with other traditional computational chemistry methodology; Hartree-Fock (HF). Summaries of the use of DFT to study both noncovalent interations and electronically excited states are also presented. In addition, the author comments on the correct application of DFT.

Chapter 2 details a computational study of the cation-π interaction of complex cations to substituted benzenes and indoles. The cation-π interaction is the electrostatic interaction between a cation and the negative electrostatic potential on an aromatic ring originating from its large permanent quadrupole moment. This chapter, in addition to establishing the correct computational parameters, establishes a large set of substituent effects with which to study cation-π interactions in vivo. These binding energy values are compared to previous applications of cation-π binding energies from our lab, and it was found that the derived binding energies are sufficiently accurate.

Chapter 3 applies the foundational knowledge from the previous chapter to study cation-π interactions of cationic ligands to multiple aromatics. This is a common motif in vivo known as the aromatic box. Using this methodology, it is established that cation binding in this form is cooperative. Further, many aromatic boxes from crystal structures were evaluated energetically.

Chapter 4 describes work to develop a new amino acid to study hydrogen bonds in Xenopus laevis oocytes. These fluorinated aliphatic amino acids inductively attenuate the hydrogen bond accepting ability of the carbonyl. This new strategy was used to probe for a hydrogen bond between the indole NH α4 TrpB and a backbone carbonyl associated with L119 on the β2 subunit of the α4β2 nicotinic acetylcholine receptor (nAChR). The fluorinated amino acids were validated computationally and with NMR studies. This new strategy showed that the α4-β2 interfacial hydrogen prediction was false.

Chapter 5 describes the synthesis and characterization of a series of meso-aromatic-acetylene cyanine dyes which feature a very large Stokes shift. Synthesis of the dyes features a key Sonagashira reaction. These dyes are investigated photophysically and computationally using time dependent DFT (TDDFT). The mechanism for this Stokes shift is an excitation to the S2 state, relaxation to the S1 state, and normal cyanine fluorescence.

Chapter 6 describes three separate strategies to construct a cyanine-based photocage to release drugs in vivo using an ortho-quinone methide strategy. One strategy utilized an acetylene-aromatic cyanine dye much like those described in Chapter 5, the second utilized an ethynyl-trimethylphenyl cation dye, and the third a photoinduced electron transfer cyanine dye. None of these strategies produced a usable photocage. The failure of these strategies are ascribed to both the short excited state lifetime of cyanine dyes and the direction of the transition dipole moment.

Finally, three appendices are presented. Appendix A describes early work to synthesize and characterize a meso-hydroxy substituted Cy5 dye. Appendix B offers many of the same computations as Chapters 2 and 3 using HF instead of DFT. Appendix C describes orbital mixing of cyanine dyes from Chapter 5 using HF instead of DFT.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:ligand cation ion channels; cation-pi interaction; aromatic box; structure-function study; cyanine dye; stokes shift; photocage; near infrared dye; time-dependent DFT
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Dougherty, Dennis A.
Thesis Committee:
  • Hsieh-Wilson, Linda C. (chair)
  • Gray, Harry B.
  • Cai, Long
  • Dougherty, Dennis A.
Defense Date:10 August 2017
Non-Caltech Author Email:davis.matthew03 (AT) gmail.com
Record Number:CaltechTHESIS:08182017-161833257
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:08182017-161833257
DOI:10.7907/Z9XK8CQF
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1039/C5CP04668HDOIArticle adapted for Chapters 2 and 3
ORCID:
AuthorORCID
Davis, Matthew Robert0000-0002-6374-4555
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:10382
Collection:CaltechTHESIS
Deposited By: Matthew Davis
Deposited On:11 Sep 2017 22:12
Last Modified:18 Sep 2017 23:32

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