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QUANTITATIVE COMPUTER-AIDED STUDIES OF ARTIFICIAL AND ENANTIOSELECTIVE ENZYMES
by
Maria P. Frushicheva
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
(CHEMISTRY)
December 2012
Copyright 2012 Maria P. Frushicheva
Object Description
| Title | Quantitative computer-aided studies of artificial and enantioselective enzymes |
| Author | Frushicheva, Maria P. |
| Author email | frushich@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Chemistry |
| School | College of Letters, Arts And Sciences |
| Date defended/completed | 2012-10-24 |
| Date submitted | 2012-11-19 |
| Date approved | 2012-11-19 |
| Restricted until | 2012-11-19 |
| Date published | 2012-11-19 |
| Advisor (committee chair) | Warshel, Arieh |
| Advisor (committee member) |
Bradforth, Stephen E. Nakano, Aiichiro |
| Abstract | A fundamental challenge in biotechnology and in biochemistry is an ability to design effective enzymes. Despite a gradual progress on this front, most of the advances have been made by placing the reacting fragments in the proper places rather than by optimizing the environment preorganization, which is the key factor in enzyme catalysis. Improving the preorganization and assessing the effectiveness of different design options requires the ability to calculate the actual catalytic effect. Current work explores the computer-aided refinement of catalytic activities (Kemp Eliminase artificial constructs and catalytic antibodies) and enantioselectivities (stereoselective Candida antarctica Lipase A enzymes) using the empirical valence bond as the main screening tool. The observed absolute catalytic effect and the effect of directed evolution experiments are reproduced and analyzed. The following refinement procedure located the mutation sites with increased catalytic activities and selectivities which have been tested experimentally. Those predictions provide a broad avenue for the design of novel catalysts. With this in mind, our approach provides a quantitative understanding of the catalytic effect of the various enzyme constructs and the results of directed evolution experiments. Furthermore, our technique provides the ability to locate the effective mutations that can increase kcat by refining the electrostatic preorganization of the protein environment, which allows us to refine and develop more efficient catalysts. |
| Keyword | artificial enzymes; catalytic reactions; computational chemistry; computer-aided enzyme design; enantioselectivity; enzymology |
| 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 | Frushicheva, Maria P. |
| 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-Frushichev-1307-0.pdf |
Description
| Title | Page 1 |
| Full text | QUANTITATIVE COMPUTER-AIDED STUDIES OF ARTIFICIAL AND ENANTIOSELECTIVE ENZYMES by Maria P. Frushicheva 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 (CHEMISTRY) December 2012 Copyright 2012 Maria P. Frushicheva |
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