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Computational enzyme design.

Bolon, Daniel N.

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Computational enzyme design.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Computational enzyme design./
Author:	Bolon, Daniel N.
Description:	124 p.
Notes:	Adviser: Stephen L. Mayo.
Contained By:	Dissertation Abstracts International63-02B.
Subject:	Biophysics, General. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3044999
ISBN:	0493587136

Computational enzyme design.
Bolon, Daniel N.

Computational enzyme design. - 124 p.

Adviser: Stephen L. Mayo.

Thesis (Ph.D.)--California Institute of Technology, 2002.

The long-term objective of computational enzyme design is the ability to generate efficient protein catalysts for any chemical reaction. This thesis develops and experimentally validates a general computational approach for the design of enzymes with novel function.

ISBN: 0493587136Subjects--Topical Terms:

1019105
Biophysics, General.

Computational enzyme design.
LDR:03304nam 2200325 a 45 001 935336
005 20110509
008 110509s2002 eng d
020 $a 0493587136
035 $a (UnM)AAI3044999
035 $a AAI3044999
040 $a UnM $c UnM
100 1 $a Bolon, Daniel N. $3 1259024
245 1 0 $a Computational enzyme design.
300 $a 124 p.
500 $a Adviser: Stephen L. Mayo.
500 $a Source: Dissertation Abstracts International, Volume: 63-02, Section: B, page: 0780.
502 $a Thesis (Ph.D.)--California Institute of Technology, 2002.
520 $a The long-term objective of computational enzyme design is the ability to generate efficient protein catalysts for any chemical reaction. This thesis develops and experimentally validates a general computational approach for the design of enzymes with novel function.
520 $a In order to include catalytic mechanism in protein design, a high-energy state (HES) rotamer (side chain representation) was constructed. In this rotamer, substrate atoms are in a HES. In addition, at least one amino acid side chain is positioned to interact favorably with substrate atoms in their HES and facilitate the reaction. Including an amino acid side chain in the HES rotamer automatically positions substrate relative to a protein scaffold and allows protein design algorithms to search for sequences capable of interacting favorably with the substrate. Because chemical similarity exists between the transition state and the high-energy state, optimizing the protein sequence to interact favorably with the HES rotamer should lead to transition state stabilization. In addition, the HES rotamer model focuses the subsequent computational active site design on a relevant phase space where an amino acid is capable of interacting in a catalytically active geometry with substrate.
520 $a Using a HES rotamer model of the histidine mediated nucleophilic hydrolysis of <italic>p</italic>-nitrophenyl acetate, the catalytically inert 108 residue <italic> E. coli</italic> thioredoxin as a scaffold, and the ORBIT protein design software to compute sequences, an active site scan identified two promising active site designs. Experimentally, both candidate “protozymes” demonstrated catalytic activity significantly above background. In addition, the rate enhancement of one of these “protozymes” was the same order of magnitude as the first catalytic antibodies.
520 $a Because polar groups are frequently buried at enzyme-substrate interfaces, improved modeling of buried polar interactions may benefit enzyme design. By studying native protein structures, rules have been developed within the scope of protein design that require core polar residues to largely satisfy their hydrogen bonding potential. Using this polar strategy to design the core of thioredoxin resulted in a protein that was thermodynamically stabilized relative to both the wt protein and a protein designed without core polar residues.
590 $a School code: 0037.
650 4 $a Biophysics, General. $3 1019105
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Computer Science. $3 626642
690 $a 0487
690 $a 0786
690 $a 0984
710 2 0 $a California Institute of Technology. $3 726902
773 0 $t Dissertation Abstracts International $g 63-02B.
790 $a 0037
790 1 0 $a Mayo, Stephen L., $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3044999