The objective of this research is to determine if a better understanding of the “molecule of life”, deoxyribonucleic acid or DNA can be obtained through Molecular Dynamics (MD) modeling and simulation (M&S) using contemporary MD M&S. It is difficult to overstate the significance of the DNA molecule. The now-completed Human Genome Project stands out as the most significant testimony yet to the importance of understanding DNA. The Human Genome Project (HGP) enumerated many areas of application of genomic research including molecular medicine, energy sources, environmental applications, agriculture and livestock breeding to name just a few. (Science, 2008) In addition to the fact that DNA contains the informational blueprints for all life, it also exhibits other remarkable characteristics most of which are either poorly understood or remain complete mysteries. One of those completely mysterious characteristics is the ability of DNA molecules to spontaneously segregate with other DNA molecules of similar sequence. This ability has been observed for years in living organisms and is known as “homologous pairing.” It is completely reproducible in a laboratory and defies explanation. What is the underlying mechanism that facilitates long-range attraction between 2 double-helix DNA molecules containing similar nucleotide sequences? The fact that we cannot answer this question indicates we are missing a fundamental piece of information concerning the DNA bio-molecule. The research proposed herein investigated using the Nano-scale Molecular Dynamics NAMD (Phillips et al., 2005) simulator the following hypotheses: H(Simulate Observed Closure NULL) : = Current MD force field models when used to model DNA molecule segments, contain sufficient variable terms and parameters to describe and reproduce iv directed segregating movement (closure of the segments) as previously observed by the Imperial College team between two Phi X 174 DNA molecules. H(Resonance NULL) : = Current MD force field models when used to model DNA molecule segments in a condensed phased solvent contain sufficient variable terms and parameters to reproduce theorized molecular resonation in the form of frequency content found in water between the segments. H(Harmonized Resonance NULL) : = Current MD force field models of DNA molecule segments in a condensed phase solvent produce theorized molecular resonation in the form of frequency content above and beyond the expected normal frequency levels found in water between the segments. H(Sequence Relationship NULL): = The specific frequencies and amplitudes of the harmonized resonance postulated in H(Harmonized Resonance NULL) are a direct function of DNA nucleotide sequence. H(Resonance Causes Closure NULL) : = Interacting harmonized resonation produces an aggregate force between the 2 macro-molecule segments resulting in simulation of the same directed motion and segment closure as observed by the Imperial College team between two Phi X 174 DNA molecules. After nearly six months of molecular dynamic simulation for H(Simulate Observed Closure NULL) and H(Resonance Causes Closure NULL) no evidence of closure between two similar sequenced DNA segments was found. There exist several contributing factors that potentially affected this result that are described in detail in the Results section. Simulations investigating H( Resonance NULL), H(Harmonized Resonance NULL) and the emergent hypothesis H(Sequence Relationship NULL) on the other hand, revealed a rich selection of periodic pressure variation occurring in the solvent between simulated DNA molecules. About v 20% of the power in Fourier coefficients returned by Fast Fourier Transforms performed on the pressure data was characterized as statistically significant and was located in less than 2% of the coefficients by count. This unexpected result occurred consistently in 5 different system configurations with considerable system-to-system variation in both frequency and magnitude. After careful analysis given the extent of our experiments the data was found to be in support of H( Resonance NULL), and H(Harmonized Resonance NULL) . Regarding the emergent hypothesis H(Sequence Relationship NULL), further analysis was done on the aggregate data set looking for correlation between nucleotide sequence and frequency/magnitude. Some of the results may be related to sequence but were insufficient to prove it. Overall the conflicting results were inconclusive so the hypothesis was neither accepted nor rejected. Of particular interest to future researchers it was noted that the computational simulations performed herein were NOT able to reproduce what we know actually happens in a laboratory environment. DNA segregation known to occur in-vitro during the Imperial College investigation did not occur in our simulation. Until this discrepancy is resolved MM simulation should not as yet be considered a suitable tool for further investigation of Homologous Chromosome Pairing. In Chapter 5 specific follow on research is described in priority of need addressing several new questions.
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Doctor of Philosophy (Ph.D.)
College of Engineering and Computer Science
Industrial Engineering and Management Systems
Modeling and Simulation
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Doctoral Dissertation (Open Access)
Dissertations, Academic -- Engineering and Computer Science, Engineering and Computer Science -- Dissertations, Academic
Calloway, Richard J., "Homologous Pairing Through Dna Driven Harmonics-- A Simulation Investigation" (2011). Electronic Theses and Dissertations, 2004-2019. 1831.