The details of the mechanism for DNA melting are fundamental to many aspects of biology and biotechnology. Recently, it has been shown experimentally that there are at least three states involved even for relatively short structures. To help clarify the reaction coordinate and mechanism of the melting transition of DNA we propose to use theoretical and computational methods. We will simulate the melting process for both free oligomer duplexes and hairpins in explicit salt water at temperatures above the sequence specific melting temperature. Analysis of the trajectories will reveal the various biochemically important processes that occur on different time scales. Augmenting this with theoretical techniques we will use the coordinates to map out free energy surfaces. An outcome of this research will be to identify plausible reaction coordinates for the melting transition. How these differ for various geometries (free oligomers vs hairpins etc.) and sequences will be useful in identifying various relevant states and kinetic traps that occur during replication, transcription, recombination, and DNA repair as well as in biotechnological applications.

Public Health Relevance

DNA melting is the process by which double-stranded DNA separates into single strands by biological means or heat or the introduction of certain chemicals. Basic research into how DNA strands couple and uncouple has tremendous relevance to issues of public health as this mechanism is important for understanding DNA mismatches, disease expression, and associated gene therapies. Research into DNA melting has direct application to the development and treatment of catastrophic diseases such as cancer, diabetes, and other genetically inherited diseases, as well as the design of gene based diagnostic tools, like DNA microarrays.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Macromolecular Structure and Function D Study Section (MSFD)
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Preusch, Peter C
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University of Texas Medical Br Galveston
Schools of Medicine
United States
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Myers, Christopher G; Pettitt, B Montgomery (2017) Phage-like packing structures with mean field sequence dependence. J Comput Chem 38:1191-1197
Esadze, Alexandre; Chen, Chuanying; Zandarashvili, Levani et al. (2016) Changes in conformational dynamics of basic side chains upon protein-DNA association. Nucleic Acids Res 44:6961-70
Chen, Chuanying; Pettitt, B Montgomery (2016) DNA Shape versus Sequence Variations in the Protein Binding Process. Biophys J 110:534-544
Bates, David; Pettitt, B Montgomery; Buck, Gregory R et al. (2016) Importance of disentanglement and entanglement during DNA replication and segregation: Comment on: ""Disentangling DNA molecules"" by Alexander Vologodskii. Phys Life Rev 18:160-164
Wang, Qian; Pettitt, B Montgomery (2016) Sequence Affects the Cyclization of DNA Minicircles. J Phys Chem Lett 7:1042-6
Wang, Qian; Myers, Christopher G; Pettitt, B Montgomery (2015) Twist-induced defects of the P-SSP7 genome revealed by modeling the cryo-EM density. J Phys Chem B 119:4937-43
Wang, Qian; Pettitt, B Montgomery (2014) Modeling DNA thermodynamics under torsional stress. Biophys J 106:1182-93
Myers, Christopher G; Pettitt, B Montgomery (2013) Communication: Origin of the contributions to DNA structure in phages. J Chem Phys 138:071103
Theruvathu, Jacob A; Yin, Y Whitney; Pettitt, B Montgomery et al. (2013) Comparison of the structural and dynamic effects of 5-methylcytosine and 5-chlorocytosine in a CpG dinucleotide sequence. Biochemistry 52:8590-8
Fogg, Jonathan M; Randall, Graham L; Pettitt, B Montgomery et al. (2012) Bullied no more: when and how DNA shoves proteins around. Q Rev Biophys 45:257-299

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