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SIMULATING THE HELICASE MOTOR OF SV40 LARGE TUMOR ANTIGEN
by
Yemin Shi
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(COMPUTATIONAL BIOLOGY AND BIOINFORMATICS)
May 2012
Copyright 2012 Yemin Shi
Object Description
| Title | Simulating the helicase motor of SV40 large tumor antigen |
| Author | Shi, Yemin |
| Author email | yeminshi@usc.edu;biostanley@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Computational Biology and Bioinformatics |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2012-05-01 |
| Date submitted | 2012-05-01 |
| Date approved | 2012-05-01 |
| Restricted until | 2012-05-01 |
| Date published | 2012-05-01 |
| Advisor (committee chair) | Chen, Xiaojiang |
| Advisor (committee member) |
Warshel, Arieh Rohs, Remo |
| Abstract | Helicases are motor protein that utilize the energy derived from NTP binding and hydrolysis to translocate and unwind DNA/RNA during the replication. Understanding the energy coupling of NTP hydrolysis cycle to the DNA movement is the key to understand the DNA replication mechanism in the molecular motor. The helicase domain of simian virus 40 large tumor antigen (SV40 LTag) is a ring-shaped AAA+ domain that participates in viral DNA replication and host cell growth control. Recent SV40 LTag structure studies have provided a set of high resolution structures in different nucleotide binding states. Hence, in this thesis we use LTag helicase as a model protein, and present the first systematic simulation study on the mechanism of the LTag helicase motor. Our work includes three major sections: first, we model the LTag ATPase activity and the helicase activity based on the biochemistry experiment results. This model indicates that the LTag helicase subunits work in highly cooperative patterns. When the origin DNA is presented, the helicase translocates DNA in a sequential pattern. When the fork DNA is added, the helicase works in a semi-sequential pattern, otherwise, the subunit cooperativity is not significant. Second, we present the first simulation study on the ATP binding/hydrolsis procedure using the non-equilibrated molecular dynamics method, the results suggest a three-stage Locker-binding model. We evaluate the energy profile using the LRA version of the semi-microscopic Protein Dipoles-Langvin Dipoles method (PDLD/S). The energy profile matches the experimental results. Thirdly, we investigate the electrostatic energy that guides the single-strand DNA (ssDNA) translocation process and propose a unidirectional translocation model. To accomplish this work, an ssDNA/LTag complex model is built using the structure information from the LTag helicase and the E1 protein-DNA complex, a two-dimensional effective electrostatic free-energy landscape is calculated based on the ssDNA/LTag model, and the unidirectional model is proposed by evaluating the energy landscape. The time dependence of the coupled protein-DNA motion is explored by simulating the translocation process using a renormalized method. Altogether, our theoretical and simulation study advanced our understanding of the fundamental molecular mechanism underlying the directional movement of ring-shaped helicase motor. |
| Keyword | computational simulation; binomial model; molecular dynamics; hHelicase motor; simian virus 40; large tumor antigen; ATP binding; DNA unwinding; DNA translocation |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Rights | Shi, Yemin |
| Access conditions | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@usc.edu |
| Archival file | uscthesesreloadpub_Volume4/etd-ShiYemin-698.pdf |
Description
| Title | Page 1 |
| Full text | SIMULATING THE HELICASE MOTOR OF SV40 LARGE TUMOR ANTIGEN by Yemin Shi A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (COMPUTATIONAL BIOLOGY AND BIOINFORMATICS) May 2012 Copyright 2012 Yemin Shi |
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