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Molecular Simulations Studies of the Effect of Ligand Architecture on DNA Binding Public Deposited

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  • In this paper we use atomistic molecular dynamics simulations to study the structural reasons underlying the DNA binding efficacy of several polyamine-aminoglycoside compounds. We calculate the free energy of binding to DNA and conformational entropy loss upon binding for spermine-aminoglycoside compounds and dilysine-aminoglycoside compounds. We also calculate the structural features of the ligands and DNA before and after binding through the radius of gyration, the width of the ligand, the end-to-end distance of the grafts, the center-of-mass distance between the DNA and the ligand, and the distance between the ligands' amine groups and the DNA's phosphate groups. In order to understand the trends in DNA binding efficacy of spermine-aminoglycoside and dilysine-aminoglycoside compounds, we compare results from polyamine-aminoglycoside systems with ungrafted polyamines (spermine and dilysine) to isolate the effects of grafting spermine and dilysine to an aminoglycoside compound on binding behavior. First, we find that grafting spermine to an aminoglycoside compound improves binding efficiency to DNA over spermine alone in agreement with the experimental results of DNA binding. We discover that the improved binding is due to a decrease in the rate of the grafts unbinding from the DNA. We also find the spermine-aminoglycoside compounds bound to DNA with a greater efficacy than the dilysine-aminoglycoside compounds. Spermine is a longer, unbranched molecule which is more flexible and adept at optimizing its binding location on the DNA strand.
Date Issued
  • 2013
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  • 2019-11-18
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