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Theoretical bioorganic chemistry of antibody catalysis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Theoretical bioorganic chemistry of antibody catalysis./
Author:	Tantillo, Dean Joseph.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2000,
Description:	172 p.
Notes:	Source: Dissertations Abstracts International, Volume: 62-04, Section: B.
Contained By:	Dissertations Abstracts International62-04B.
Subject:	Biochemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9973169
ISBN:	9780599787506

Theoretical bioorganic chemistry of antibody catalysis.
Tantillo, Dean Joseph.

Theoretical bioorganic chemistry of antibody catalysis. - Ann Arbor : ProQuest Dissertations & Theses, 2000 - 172 p.

Source: Dissertations Abstracts International, Volume: 62-04, Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2000.

This item must not be sold to any third party vendors.

This dissertation describes computational studies aimed at elucidating the mechanisms of catalysis employed by antibodies that promote the hydrolysis of aryl esters and the decarboxylation of carboxybenzisoxazoles. Chapter 1 provides an introduction to relevant aspects of antibody biology and biochemistry, as well as a brief introduction to theoretical methods that have been applied to antibody modeling. Chapter 2 provides a description of a particular theoretical methodology-the "theozyme" technique-that is applied to a specific problem in antibody catalysis in Chapter 5. Chapters 3 and 4 describe computations on the alkaline hydrolyses of aryl esters in the gas phase, in solution, and in the combining sites of various antibody catalysts. Intermediates and transition states involved in gas phase hydrolysis were investigated using ab initio calculations. The structures of these species were then compared with those of phosphonate transition state analogs used as haptens to elicit hydrolytic antibodies; although many similarities were observed, several important differences were noted. Computed transition states were then docked into the crystallographically-determined structures of various hydrolytic antibodies using a Monte Carlo simulated annealing technique. These experiments correlated observed rate variations with subtle differences in the identities and orientations of hydrogen bond donor and acceptor groups that interact with the hydrolytic transition states. Chapter 5 describes a similar treatment of the antibody-promoted decarboxylation of 3-carboxybenzisoxazoles, a reaction that has been of interest to chemists for decades due to its tremendous acceleration in nonpolar and polar aprotic environments versus reaction in aqueous solution. The structure of an antibody that catalyzes this reaction was recently obtained by the research groups of Donald Hilvert and Ian Wilson, and based on these crystallographic studies-and in collaboration with Hilvert and Wilson-a combination of quantum mechanical and docking calculations were used to explore the origins of catalysis by this antibody decarboxylase. Chapter 6 describes investigations into the nature of the immune response leading to catalysts for hydrolysis and decarboxylation, using bioinformatic and docking strategies, which suggest that the naive antibody repertoire may contain generic binding sites capable of binding many different molecules that contain tetrahedral anionic substructures.

ISBN: 9780599787506Subjects--Topical Terms:

518028
Biochemistry.
Subjects--Index Terms:

Antibody

Theoretical bioorganic chemistry of antibody catalysis.
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100 1 $a Tantillo, Dean Joseph. $3 3686214
245 1 0 $a Theoretical bioorganic chemistry of antibody catalysis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2000
300 $a 172 p.
500 $a Source: Dissertations Abstracts International, Volume: 62-04, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Houk, Kendall N.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2000.
506 $a This item must not be sold to any third party vendors.
506 $a This item must not be added to any third party search indexes.
520 $a This dissertation describes computational studies aimed at elucidating the mechanisms of catalysis employed by antibodies that promote the hydrolysis of aryl esters and the decarboxylation of carboxybenzisoxazoles. Chapter 1 provides an introduction to relevant aspects of antibody biology and biochemistry, as well as a brief introduction to theoretical methods that have been applied to antibody modeling. Chapter 2 provides a description of a particular theoretical methodology-the "theozyme" technique-that is applied to a specific problem in antibody catalysis in Chapter 5. Chapters 3 and 4 describe computations on the alkaline hydrolyses of aryl esters in the gas phase, in solution, and in the combining sites of various antibody catalysts. Intermediates and transition states involved in gas phase hydrolysis were investigated using ab initio calculations. The structures of these species were then compared with those of phosphonate transition state analogs used as haptens to elicit hydrolytic antibodies; although many similarities were observed, several important differences were noted. Computed transition states were then docked into the crystallographically-determined structures of various hydrolytic antibodies using a Monte Carlo simulated annealing technique. These experiments correlated observed rate variations with subtle differences in the identities and orientations of hydrogen bond donor and acceptor groups that interact with the hydrolytic transition states. Chapter 5 describes a similar treatment of the antibody-promoted decarboxylation of 3-carboxybenzisoxazoles, a reaction that has been of interest to chemists for decades due to its tremendous acceleration in nonpolar and polar aprotic environments versus reaction in aqueous solution. The structure of an antibody that catalyzes this reaction was recently obtained by the research groups of Donald Hilvert and Ian Wilson, and based on these crystallographic studies-and in collaboration with Hilvert and Wilson-a combination of quantum mechanical and docking calculations were used to explore the origins of catalysis by this antibody decarboxylase. Chapter 6 describes investigations into the nature of the immune response leading to catalysts for hydrolysis and decarboxylation, using bioinformatic and docking strategies, which suggest that the naive antibody repertoire may contain generic binding sites capable of binding many different molecules that contain tetrahedral anionic substructures.
590 $a School code: 0031.
650 4 $a Biochemistry. $3 518028
650 4 $a Organic chemistry. $3 523952
653 $a Antibody
653 $a Aryl esters
653 $a Carboxybenzisoxazoles
653 $a Hydrolytic antibodies
690 $a 0487
690 $a 0490
710 2 $a University of California, Los Angeles. $3 626622
773 0 $t Dissertations Abstracts International $g 62-04B.
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791 $a Ph.D.
792 $a 2000
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=9973169