THESIS
2017
98 pages : illustrations (some color) ; 30 cm
Abstract
DNA methylation in the form 5-methylcytosine (5mC) plays an important role in epigenetic
regulations. The methylated base can be stepwise oxidized to 5-hydroxylcytosine (5hmC), 5-fomylcytosine (5fC) and 5-carboxylcytosine (5caC). Crystal structure of RNA polymerase II (Pol II) elongation complex shows the 5caC nucleobase in DNA template strand can be recognized
with a midway conformation above the bridge helix by forming hydrogen bonds with Rpb2
residue Q531 sidechain. With the molecular dynamics (MD) simulation trajectories of RNA
Polymerase II elongation complex with 5caC modification on the i+1 site of the DNA template
strand, we built a Markov State Model to study the mechanism for Pol II translocation with the
5caC base modification. While constructing the model, we implement...[
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DNA methylation in the form 5-methylcytosine (5mC) plays an important role in epigenetic
regulations. The methylated base can be stepwise oxidized to 5-hydroxylcytosine (5hmC), 5-fomylcytosine (5fC) and 5-carboxylcytosine (5caC). Crystal structure of RNA polymerase II (Pol II) elongation complex shows the 5caC nucleobase in DNA template strand can be recognized
with a midway conformation above the bridge helix by forming hydrogen bonds with Rpb2
residue Q531 sidechain. With the molecular dynamics (MD) simulation trajectories of RNA
Polymerase II elongation complex with 5caC modification on the i+1 site of the DNA template
strand, we built a Markov State Model to study the mechanism for Pol II translocation with the
5caC base modification. While constructing the model, we implemented time-structure
Independent Component Analysis (tICA) to select the features for geometric clustering, and used
projection operator approach to optimize lumping and reconstruct the macrostate model.
According to the reconstructed model, the translocation of 5caC system follows the Brownian
rechet mechanism, but the conformational transitions of Pol II in the post-translocation free
energy basin are greatly slowed down in comparison to the wild type system. This significant
difference in timescale is caused by the presence of several newly identified intermediate states.
With the constantly existence of hydrogen bonds between COO- on 5caC and Rpb2 residue
Q531 on fork loop 3, all the macrostates are stabilized, which increases the timescale of
translocation. Our model provides novel structural dynamic insights in how Pol II is arrested by
epigenetic modifications.
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