Author ORCID Identifier

https://orcid.org/0000-0002-5083-0614

Date of Award

12-10-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Ivaylo Ivanov

Second Advisor

Donald Hamelberg

Third Advisor

W. David Wilson

Fourth Advisor

Irene Weber

Abstract

The recognition of specific DNA sequences is fundamental to the central dogma of molecular biology wherein DNA is transcribed to RNA and RNA is translated to protein. Without the ability to recognize specific target sties errors in transcription occur that can result in detrimental mutations and disease. Through the use of molecular dynamics and biophysical computational methods, it is possible to investigate the interactions between nucleic acids other biomolecules at the atomistic level. This leads to a physical interpretation of the underlying mechanics of these crucial interactions. In this dissertation two biomolecules that interact specifically with the minor groove of DNA have been investigated. DB2277, a dication diamidine, inserts into the minor groove, recognizing a specific DNA sequence with high specificity. The combination of shape complementarity and direct contacts between the DNA base pairs aids in its ability to distinguish its preferred sequence. Understanding the driving force behind DNA sequence recognition could aid in the development of transcription sequence specific therapeutics for the treatment of disease. On a much larger scale, the macromolecule DNA sliding clamp uses the minor groove as a guide as it diffuses along the DNA backbone. The unique electrostatic configuration of inner pore allows it to modulate the diffusion. Insight into protein propagation along the DNA backbone could provide a great understanding into how proteins locate their target binding sites. Although both of these complexes interact with DNA in two very different ways, it is the intrinsic nature of the DNA that allows them to do so. It is this relationship which is explored throughout the dissertation.

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